Antisense Oligonucleotides Targeting ATXN3

ABSTRACT

The present invention relates to antisense LNA oligonucleotides (oligomers) complementary to ATXN3 pre-mRNA sequences, which are capable of inhibiting the expression of ATXN3 protein. Inhibition of ATXN3 expression is beneficial for the treatment of spinocerebellar ataxia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of and priority to the European PatentApplication EP 20211618.2 filed on Dec. 3, 2020, all of which areincorporated by reference in their entireties where permissible.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to antisense LNA oligonucleotides(oligomers) complementary to ATXN3 pre-mRNA sequences, which are capableof inhibiting the expression of ATXN3. Inhibition of ATXN3 expression isbeneficial for the treatment of spinocerebellar ataxia, such asspinocerebellar ataxia 3 (Machado-Joseph disease (MJD)).

REFERENCE TO SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Dec. 3, 2020, isnamed 067211_015US1 SL.txt and is 614,400 bytes in size.

BACKGROUND OF THE INVENTION

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Josephdisease (MJD), is one of nine polyglutamine expansion diseases and themost common dominantly inherited ataxia in the world. While certainsymptoms in SCA3 may respond to symptomatic therapy, there is still noeffective treatment for this relentlessly progressive and fatalneurodegenerative disease. The disease is caused by a CAG repeatexpansion in the ATXN3 gene that encodes an abnormally longpolyglutamine tract in the disease protein, ATXN3 (Ataxin 3). The toxicataxin-3 protein is associated with aggregates which are frequentlyobserved in the brain tissue of SCA3 patients.

Moore et al. reported that antisense oligonucleotides (ASOs) targetingATXN3 were capable of reducing levels of the pathogenic ATXN3 proteinboth in human disease fibroblasts and in a mouse model expressing thefull-length human mutant ATXN3 gene (Moore et al., Mol Ther NucleicAcids. 2017; 7:200-210). Therefore, ASO-mediated targeting of ATXN3 wassuggested as therapeutic approach for SCA3.

Swayze et al. (Nucleic Acids Res. 2007; 35(2):687-700. Epub 2006 Dec.19), reports that antisense oligonucleotides containing locked nucleicacid have the potential to improve potency but cause significanttoxicity in animals (hepatotoxicity).

Toonen et al. used antisense oligonucleotides to mask predicted exonicsplicing signals of ATXN3, resulting in exon 10 skipping from ATXN3pre-mRNA. The skipping of exon 10 led to formation of a truncatedataxin-3 protein lacking the toxic polyglutamine expansion, butretaining its ubiquitin binding and cleavage function (Toonen et al.,Molecular Therapy—Nucleic Acids, 2017, Volume 8: 232-242).

WO2013/138353, WO2015/017675, WO2018/089805, WO2019/217708 andWO2020/172559 disclose antisense oligonucleotides targeting human ATXN3mRNA for use in the treatment of SCA3.

SUMMARY OF THE INVENTION

The present invention identifies regions of the ATXN3 transcript (ATXN3)for antisense inhibition in vitro or in vivo, and provides for antisenseoligonucleotides, including LNA gapmer oligonucleotides, which targetthese regions of the ATXN3 pre-mRNA or mature mRNA. Particularly, thepresent invention identifies antisense oligonucleotides which targethuman ATXN3 pre-mRNA or mature mRNA more effectively than they targetthe human Potassium Voltage-Gated Channel Subfamily B Member 2 (KCNB2)pre-mRNA or mature mRNA. The present invention identifiesoligonucleotides which inhibit human ATXN3 which are useful in thetreatment of spinocerebellar ataxia.

The invention provides for an antisense oligonucleotide, 10-30nucleotides in length, targeting a mammalian ATXN3 (Ataxin 3) targetnucleic acid, wherein the antisense oligonucleotide is capable ofinhibiting the expression of mammalian ATXN3 in a cell which isexpressing mammalian ATXN3. The mammalian ATXN3 target nucleic acid maybe, e.g., a human, monkey or mouse ATXN3 target nucleic acid.

The invention also provides for an LNA gapmer antisense oligonucleotide,10-30 nucleotides in length, wherein said antisense oligonucleotidecomprises a contiguous nucleotide sequence 10-30 nucleotides in length,wherein the contiguous nucleotide sequence is at least 90%complementary, such as fully complementary, to SEQ ID NO:1, wherein theantisense oligonucleotide is capable of inhibiting the expression ofhuman ATXN3 in a cell which is expressing human ATXN3.

In one aspect, the invention provides for an antisense oligonucleotidecomprising a contiguous nucleotide sequence comprising the contiguousnucleotides present in SEQ ID NO:1122 except for one or more modifiednucleosides and/or one or more modified internucleoside linkages,wherein the antisense oligonucleotide is capable of inhibiting theexpression of human ATXN3 in a cell which is expressing human ATXN3; ora pharmaceutically acceptable salt thereof. In some embodiments, theantisense oligonucleotide is more capable of inhibiting the expressionof human ATXN3 than human KCNB2 in a cell which is expressing humanATXN3 and human KCNB2. In some embodiments, the one or more modifiednucleosides and/or one or more modified internucleoside linkages are,for each residue in SEQ ID NO:1122, independently selected from theoptions for that residue as shown in Table 15.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising at least 10, such as at least12, such as at least 14, such as at least 16 contiguous nucleotidespresent in SEQ ID NO:1122. In some embodiments, the antisenseoligonucleotide comprises the contiguous nucleotide sequence of SEQ IDNO: 1122.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising the base sequence of anantisense oligonucleotide selected from the group consisting of CompoundID Nos. 1122_82 to 1122_336, shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising the nucleoside base sequenceand, optionally, the sugar moiety modifications, of an antisenseoligonucleotide selected from the group consisting of Compound ID Nos.1122_91, 1122_107, 1122_154, 1122_155, 1122_156, 1122_157, 1122_158,1122_167, 1122_172, 1122_175, 1122_294, and 1122_296, shown in Table 14.

In some embodiments, the antisense oligonucleotide is an LNA gapmerantisense oligonucleotide; or a pharmaceutically acceptable saltthereof. Typically, each LNA cytosine is an LNA 5-methyl cytosine.

In some embodiments, substantially all, or all, internucleoside linkagesbetween the nucleosides are phosphorothioate internucleoside linkages.In some particular embodiments, one or more of the phosphothioateinternucleoside linkages are stereodefined.

In some embodiments, one or more nucleosides are also or alternativelymodified to a 2′-sugar-modified nucleoside.

In some embodiments, one or more cytosine nucleosides are also oralternatively modified to a 5-methyl cytosine nucleoside.

In some embodiments, one or more thymine nucleosides are modified to auracil nucleoside.

In one aspect, the invention provides for an antisense oligonucleotidecomprising a contiguous nucleotide sequence comprising the contiguousnucleotides present in SEQ ID NO:1816 except for one or more modifiednucleosides and/or one or more modified internucleoside linkages,wherein the antisense oligonucleotide is capable of inhibiting theexpression of human ATXN3 in a cell which is expressing human ATXN3; ora pharmaceutically acceptable salt thereof. In some embodiments, theantisense oligonucleotide is more capable of inhibiting the expressionof human ATXN3 than human KCNB2 in a cell which is expressing humanATXN3 and human KCNB2. In some embodiments, the one or more modifiednucleosides and/or one or more modified internucleoside linkages are,for each residue in SEQ ID NO:1816, independently selected from theoptions for that residue as shown in Table 16.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising at least 10, such as at least12, such as at least 14, such as at least 16 contiguous nucleotidespresent in SEQ ID NO:1816. In some embodiments, the antisenseoligonucleotide comprises the contiguous nucleotide sequence of SEQ IDNO: 1816.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising the base sequence of anantisense oligonucleotide selected from the group consisting of CompoundID Nos. 1816_2 to 1816_74, shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises thenucleoside base sequence and, optionally, the sugar moietymodifications, of an antisense oligonucleotide selected from the groupconsisting of Compound ID Nos. 1816_13, 1816_15, 1816_28, 1816_41,1816_42, 1816_43, 1816_60, 1816_61, 1816_64, 1816_65, and 1816_68, asshown in Table 14.

In some embodiments, the antisense oligonucleotide is an LNA gapmerantisense oligonucleotide; or a pharmaceutically acceptable saltthereof. Typically, each LNA cytosine is an LNA 5-methyl cytosine.

In some embodiments, substantially all, or all, internucleoside linkagesbetween the nucleosides are phosphorothioate internucleoside linkages.In some particular embodiments, one or more of the phosphothioateinternucleoside linkages are stereodefined.

In some embodiments, one or more nucleosides are also or alternativelymodified to a 2′-sugar-modified nucleoside.

In some embodiments, one or more cytosine nucleosides are also oralternatively modified to a 5-methyl cytosine nucleoside.

In some embodiments, one or more thymine nucleosides are modified to auracil nucleoside.

More details on these or other nucleoside modifications and/orinternucleoside linkage modifications are provided in the presentdisclosure.

In one aspect, the invention provides for the antisense oligonucleotidesdisclosed herein, for example an antisense oligonucleotide selected fromthe group consisting of the compounds shown in the table in Example 13;or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides for the antisense oligonucleotidedisclosed herein, for example an antisense oligonucleotide selected fromthe group consisting of the compounds shown in Table 11; or apharmaceutically acceptable salt thereof.

In some embodiments, the antisense oligonucleotide is selected from thegroup consisting of the compounds shown in the table in Example 16.

In some embodiments, the antisense oligonucleotide is selected from thegroup consisting of the compounds shown in Table 14.

In one aspect, the invention particularly provides for an antisenseoligonucleotide selected from the group consisting of Compound ID Nos.1122_91, 1122_107, 1122_154, 1122_155, 1122_156, 1122_157, 1122_158,1122_167, 1122_172, 1122_175, 1122_294, 1122_296, 1816_13, 1816_15,1816_28, 1816_41, 1816_42, 1816_43, 1816_60, 1816_61, 1816_64, 1816_65,and 1816_68; or a pharmaceutically acceptable salt thereof.

In separate and specific aspects, the invention provides for anantisense oligonucleotide as shown in FIG. 12A, 12B, 12C, 12D, 12E, 12F,12G, 12H, 12I, 12J, 12K, 12L, 12M, 12N, 12O, 12P, 12Q, 12R, 12S, 12T,12U, 12V, or 12W; or a pharmaceutically acceptable salt thereof. Aoligonucleotide of the invention as referred to or claimed herein may bein the form of a pharmaceutically acceptable salt, such as a sodium orpotassium salt.

In one aspect, the invention provides for a conjugate comprising anoligonucleotide according to the invention, and at least one conjugatemoiety covalently attached to said oligonucleotide.

In one aspect, the invention provides for a pharmaceutical compositioncomprising the oligonucleotide or conjugate of the invention and apharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.

In one aspect, the invention provides for an in vivo or in vitro methodfor modulating ATXN3 expression in a target cell which is expressingATXN3, said method comprising administering an oligonucleotide orconjugate or pharmaceutical composition of the invention in an effectiveamount to said cell.

In one aspect, the invention provides for a method for treating orpreventing a disease comprising administering a therapeutically orprophylactically effective amount of an oligonucleotide, conjugate orthe pharmaceutical composition of the invention to a subject sufferingfrom or susceptible to the disease.

In some embodiments, the disease is spinocerebellar ataxia, such asspinocerebellar ataxia 3, such as Machado-Joseph disease (MJD).

In one aspect, the invention provides for the oligonucleotide, conjugateor the pharmaceutical composition of the invention for use in medicine.

In one aspect, the invention provides for the oligonucleotide, conjugateor the pharmaceutical composition of the invention for use in thetreatment or prevention of spinocerebellar ataxia, such asspinocerebellar ataxia 3, such as Machado-Joseph disease (MJD).

In one aspect, the invention provides for the use of theoligonucleotide, conjugate or the pharmaceutical composition of theinvention, for the preparation of a medicament for treatment orprevention of spinocerebellar ataxia, such as spinocerebellar ataxia 3such as Machado-Joseph disease (MJD).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays a drawing of the compound 1122_67 (SEQ ID NO:1122).

FIG. 2 displays a drawing of the compound 1813_1 (SEQ ID NO:1813).

FIG. 3 displays a drawing of the compound 1856_1 (SEQ ID NO:1856).

FIG. 4 displays a drawing of the compound 1812_1 (SEQ ID NO:1812).

FIG. 5 displays a drawing of the compound 1809_2 (SEQ ID NO:1809).

FIG. 6 displays a drawing of the compound 1607_1 (SEQ ID NO:1607).

FIG. 7 displays a drawing of the compound 1122_62 (SEQ ID NO:1122).

FIG. 8 displays a drawing of the compound 1122_33 (SEQ ID NO:1122).

FIG. 9 portrays the stability of the compounds 1122_67 and 1813_1, and 5reference compounds (i.e. compounds 1100673, 1101657, 1102130, 1103014,and 1102987) in a 24 hour SVPD assay.

FIG. 10A displays a WES analysis of GM06153 cells treated with differentASOs to obtain reduction of wild type Ataxin 3 (55 kDa) and polyQextended Ataxin 3 (77 kDa). FIG. 10B displays an analysis of bandintensity normalized to HPRT. Wild type Ataxin 3 is represented by theband at 55 kDa, and the polyQ extended Ataxin 3 is represented by theband at 77 kDa. Cells have been treated with 10 uM of ASO for 4 daysprior to protein analysis. Data represents cells treated with ASOs intriplicates as mean+-SD. SC, scrambled control oligo.

FIG. 11 displays a drawing of the compound 1816_12.

FIGS. 12A-W display drawings of the compounds in Table 14 (Example 16).FIG. 12A displays a drawing of compound 1122_91. FIG. 12B displays adrawing of compound 1122_107. FIG. 12C displays a drawing of compound1122_154. FIG. 12D displays a drawing of compound 1122_155. FIG. 12Edisplays a drawing of compound 1122_156. FIG. 12F displays a drawing ofcompound 1122_157. FIG. 12G displays a drawing of compound 1122_158.FIG. 12H displays a drawing of compound 1122_167. FIG. 12I displays adrawing of compound 1122_172. FIG. 12J displays a drawing of compound1122_175. FIG. 12K displays a drawing of compound 1122_294. FIG. 12Ldisplays a drawing of compound 1122_296. FIG. 12M displays a drawing ofcompound 1816_13. FIG. 12N displays a drawing of compound 1816_15. FIG.12O displays a drawing of compound 1816_28. FIG. 12P displays a drawingof compound 1816_41. FIG. 12Q displays a drawing of compound 1816_42.FIG. 12R displays a drawing of compound 1816_43. FIG. 12S displays adrawing of compound 1816_60. FIG. 12T displays a drawing of compound1816_61. FIG. 12U displays a drawing of compound 1816_64. FIG. 12Vdisplays a drawing of compound 1816_65. FIG. 12W displays a drawing ofcompound 1816_68.

The chemical drawings show the protonated form of the antisenseoligonucleotide, and it will be understood that each hydrogen on thesulphur atom in the phosphorothioate intemucleoside linkage mayindependently be present or absent. In a salt form, one or more more ofthe hydrogens may for example be replaced with a cation, such as a metalcation, such as a sodium cation or a potassium cation.

FIG. 13 displays an image showing raw results from the WES analysis ofprotein level. Included are compounds 1605_4, 1122_107, 1122_156 and ascrambled control oligo.

FIG. 14 displays an image showing raw results from the WES analysis ofprotein level. Included are compounds 1287095, 1102579, 1605_2 and ascrambled control oligo.

FIG. 15 displays an analysis of band intensity normalized to HPRT. Cellshave been treated with 5 μM of ASO for 4 days prior to protein analysis.Data represents cells treated with ASOs in triplicates as mean+-SD. *p-value<0.05; ** p-value<0.01.

FIG. 16 displays a WES analysis of SK-N-AS cells treated with differentASOs to obtain reduction of wild type Ataxin 3 (55 kDa). The loadingcontrol used for normalization was HPRT.

FIG. 17 displays a WES analysis of SK-N-AS cells treated with differentreference compound ASOs to obtain reduction of wild type Ataxin 3 (55kDa). The loading control used for normalization was HPRT.

FIG. 18 displays an analysis of band intensity normalized to HPRT. Cellswere treated with 5 or 15 uM of ASO for 4 days prior to proteinanalysis. Data represents cells treated with ASOs in triplicates asmean+-SD.

FIG. 19 displays results from ddPCR analysis showing remaining level ofATXN3 mRNA following treatment with the listed compounds.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

It should be appreciated that this disclosure is not limited to thecompositions and methods described herein as well as the experimentalconditions described, as such may vary. It is also to be understood thatthe terminology used herein is for the purpose of describing certainembodiments only, and is not intended to be limiting, since the scope ofthe present disclosure will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any compositions,methods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention. Allpublications mentioned are incorporated herein by reference in theirentirety.

The use of the terms “a,” “an,” “the,” and similar referents in thecontext of describing the presently claimed invention (especially in thecontext of the claims) are to be construed to cover both the singularand the plural, unless otherwise indicated herein or clearlycontradicted by context.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

Use of the term “about” is intended to describe values either above orbelow the stated value in a range of approx. +/−10%; in otherembodiments the values may range in value either above or below thestated value in a range of approx. +/−5%; in other embodiments thevalues may range in value either above or below the stated value in arange of approx. +/−2%; in other embodiments the values may range invalue either above or below the stated value in a range of approx.+/−1%. The preceding ranges are intended to be made clear by context,and no further limitation is implied. All methods described herein canbe performed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

As used herein, the terms “treat,” “treating,” “treatment” and“therapeutic use” refer to the elimination, reduction or amelioration ofone or more symptoms of a disease or disorder. Specifically, the term“treatment” may refer to both treatment of an existing disease (e.g. adisease or disorder as herein referred to), or prevention of a disease(i.e. prophylaxis). It will therefore be recognized that treatment asreferred to herein may, in some embodiments, be prophylactic. As usedherein, a “therapeutically effective amount” refers to that amount of atherapeutic agent sufficient to mediate a clinically relevantelimination, reduction or amelioration of such symptoms. An effect isclinically relevant if its magnitude is sufficient to impact the healthor prognosis of a recipient subject. A therapeutically effective amountmay refer to the amount of therapeutic agent sufficient to delay orminimize the onset of disease. A therapeutically effective amount mayalso refer to the amount of the therapeutic agent that provides atherapeutic benefit in the treatment or management of a disease.

The term “oligonucleotide” as used herein is defined as it is generallyunderstood by the skilled person as a molecule comprising two or morecovalently linked nucleosides. Such covalently bound nucleosides mayalso be referred to as nucleic acid molecules or oligomers.Oligonucleotides are commonly made in the laboratory by solid-phasechemical synthesis followed by purification. When referring to asequence of the oligonucleotide, reference is made to the sequence ororder of nucleobase moieties, or modifications thereof, of thecovalently linked nucleotides or nucleosides. The oligonucleotide of theinvention is man-made, and is chemically synthesized, and is typicallypurified or isolated. The oligonucleotide of the invention may compriseone or more modified nucleosides or nucleotides.

The term “Antisense oligonucleotide” as used herein is defined asoligonucleotides capable of modulating expression of a target gene byhybridizing to a target nucleic acid, in particular to a contiguoussequence on a target nucleic acid. The antisense oligonucleotides arenot essentially double stranded and are therefore not siRNAs or shRNAs.Preferably, the antisense oligonucleotides of the present invention aresingle stranded. It is understood that single stranded oligonucleotidesof the present invention can form hairpins or intermolecular duplexstructures (duplex between two molecules of the same oligonucleotide),as long as the degree of intra or inter self-complementarity is lessthan 50% across of the full length of the oligonucleotide.

The term “contiguous nucleotide sequence” refers to the region of theoligonucleotide which is complementary to the target nucleic acid. Theterm is used interchangeably herein with the term “contiguous nucleobasesequence” and the term “oligonucleotide motif sequence” also refered toas “motif sequence”. The “motif sequence” may also be referred to as the“Oligonucleotide Base Sequence”. In some embodiments all the nucleotidesof the oligonucleotide constitute the contiguous nucleotide sequence. Insome embodiments the oligonucleotide comprises the contiguous nucleotidesequence, such as a F-G-F′ gapmer region, and may optionally comprisefurther nucleotide(s), for example a nucleotide linker region which maybe used to attach a functional group to the contiguous nucleotidesequence. The nucleotide linker region may or may not be complementaryto the target nucleic acid. Advantageously, the contiguous nucleotidesequence is 100% complementary to the target nucleic acid.

The term “modified oligonucleotide” describes an oligonucleotidecomprising one or more modified nucleosides and/or modifiedinternucleoside linkages. The term chimeric” oligonucleotide is a termthat has been used in the literature to describe oligonucleotides withmodified nucleosides.

The term “nucleotides” refers to the building blocks of oligonucleotidesand polynucleotides, and for the purposes of the present inventioninclude both naturally occurring and non-naturally occurringnucleotides. In nature, nucleotides, such as DNA and RNA nucleotidescomprise a ribose sugar moiety, a nucleobase moiety and one or morephosphate groups (which is absent in nucleosides). Nucleosides andnucleotides may also interchangeably be referred to as “units” or“monomers”.

The term “nucleobase” refers to the purine (e.g. adenine and guanine)and pyrimidine (e.g. uracil, thymine and cytosine) moieties present innucleosides and nucleotides which form hydrogen bonds in nucleic acidhybridization. In the context of the present invention the termnucleobase also encompasses modified nucleobases which may differ fromnaturally occurring nucleobases, but are functional during nucleic acidhybridization. In this context “nucleobase” refers to both naturallyoccurring nucleobases such as adenine, guanine, cytosine, thymidine,uracil, xanthine and hypoxanthine, as well as non-naturally occurringvariants. Such variants are for example described in Hirao et al (2012)Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009)Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In some embodiments, the “nucleobase moiety” is modified by changing thepurine or pyrimidine into a modified purine or pyrimidine, such assubstituted purine or substituted pyrimidine, such as a nucleobasedselected from isocytosine, pseudoisocytosine, 5-methyl cytosine,5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil,5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine,diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and2-chloro-6-aminopurine.

The nucleobase moieties may be indicated by the letter code for eachcorresponding nucleobase, e.g. A, T, G, C or U, wherein each letter mayoptionally include modified nucleobases of equivalent function. Forexample, in the exemplified oligonucleotides, the nucleobase moietiesare selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNAgapmers, 5-methyl cytosine LNA nucleosides may be used.

The term “modified nucleoside” or “nucleoside modification” as usedherein refers to nucleosides modified as compared to the equivalent DNAor RNA nucleoside by the introduction of one or more modifications ofthe sugar moiety or the (nucleo) base moiety. In a preferred embodiment,the modified nucleoside comprises a modified sugar moiety. The termmodified nucleoside may also be used herein interchangeably with theterm “nucleoside analogue” or modified “units” or modified “monomers”.Nucleosides with an unmodified DNA or RNA sugar moiety are termed DNA orRNA nucleosides herein. Nucleosides with modifications in the baseregion of the DNA or RNA nucleoside are still generally termed DNA orRNA if they allow Watson Crick base pairing.

The oligomer of the invention may comprise one or more nucleosides whichhave a modified sugar moiety, i.e. a modification of the sugar moietywhen compared to the ribose sugar moiety found in DNA and RNA.

Numerous nucleosides with modification of the ribose sugar moiety havebeen made, primarily with the aim of improving certain properties ofoligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include those where the ribose ring structure ismodified, e.g. by replacement with a hexose ring (HNA), or a bicyclicring, which typically have a biradicle bridge between the C2 and C4carbons on the ribose ring (LNA), or an unlinked ribose ring whichtypically lacks a bond between the C2 and C3 carbons (e.g. UNA). Othersugar modified nucleosides include, for example, bicyclohexose nucleicacids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798).Modified nucleosides also include nucleosides where the sugar moiety isreplaced with a non-sugar moiety, for example in the case of peptidenucleic acids (PNA), or morpholino nucleic acids.

As used herein, “sugar modifications” also include modifications madevia altering the substituent groups on the ribose ring to groups otherthan hydrogen, or the 2′—OH group naturally found in DNA and RNAnucleosides. Substituents may, for example be introduced at the 2′, 3′,4′ or 5′ positions.

As used herein, a “2′ sugar modified nucleoside” refers to a nucleosidewhich has a substituent other than H or OH at the 2′ position (2′substituted nucleoside) or comprises a 2′ linked biradicle capable offorming a bridge between the 2′ carbon and a second carbon in the ribosering, such as LNA (2′ 4′ biradicle bridged) nucleosides.

Indeed, much focus has been spent on developing 2′ substitutednucleosides, and numerous 2′ substituted nucleosides have been found tohave beneficial properties when incorporated into oligonucleotides. Forexample, the 2′ modified sugar may provide enhanced binding affinityand/or increased nuclease resistance to the oligonucleotide. Examples of2′ substituted modified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA,2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA,and 2′-F-ANA nucleoside. For further examples, please see e.g. Freier &Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinionin Drug Development, 2000, 3(2), 293-213, and Deleavey and Damha,Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2′substituted modified nucleosides.

In relation to the present invention 2′ substituted does not include 2′bridged molecules like LNA.

As used herein, a “Locked Nucleic Acid (LNA) nucleoside” is a2′-modified nucleoside which comprises a biradical linking the C2′ andC4′ of the ribose sugar ring of said nucleoside (also referred to as a“2′-4′ bridge”), which restricts or locks the conformation of the ribosering. These nucleosides are also termed bridged nucleic acid or bicyclicnucleic acid (BNA) in the literature. The locking of the conformation ofthe ribose is associated with an enhanced affinity of hybridization(duplex stabilization) when the LNA is incorporated into anoligonucleotide for a complementary RNA or DNA molecule. This can beroutinely determined by measuring the melting temperature of theoligonucleotide/complement duplex.

Non limiting, exemplary LNA nucleosides are disclosed in WO 99/014226,WO 00/66604, WO 98/039352, WO 2004/046160, WO 00/047599, WO 2007/134181,WO 2010/077578, WO 2010/036698, WO 2007/090071, WO 2009/006478, WO2011/156202, WO 2008/154401, WO 2009/067647, WO 2008/150729, Morita etal., Bioorganic & Med. Chem. Lett. 12, 73-76, Seth et al. J. Org. Chem.2010, Vol 75(5) pp. 1569-81, and Mitsuoka et al., Nucleic Acids Research2009, 37(4), 1225-1238, and Wan and Seth, J. Medical Chemistry 2016, 59,9645-9667.

Further non limiting, exemplary LNA nucleosides are disclosed in Scheme1:

Particular LNA nucleosides are beta-D-oxy-LNA, 6′-methyl-beta-D-oxy LNAsuch as (S)-6′-methyl-beta-D-oxy-LNA (ScET) and ENA. A particularlyadvantageous LNA is beta-D-oxy-LNA.

As used herein, the term “modified internucleoside linkage” is definedas generally understood by the skilled person as linkages other thanphosphodiester (PO) linkages, that covalently couples two nucleosidestogether. The oligonucleotides of the invention may therefore comprisemodified internucleoside linkages. In some embodiments, the modifiedinternucleoside linkage increases the nuclease resistance of theoligonucleotide compared to a phosphodiester linkage. For naturallyoccurring oligonucleotides, the internucleoside linkage includesphosphate groups creating a phosphodiester bond between adjacentnucleosides.

Modified internucleoside linkages are particularly useful in stabilizingoligonucleotides for in vivo use, and may serve to protect againstnuclease cleavage at regions of DNA or RNA nucleosides in theoligonucleotide of the invention, for example within the gap region of agapmer oligonucleotide, as well as in regions of modified nucleosides,such as region F and F′. In an embodiment, the oligonucleotide comprisesone or more internucleoside linkages modified from the naturalphosphodiester, such one or more modified internucleoside linkages thatis for example more resistant to nuclease attack. Nuclease resistancemay be determined by incubating the oligonucleotide in blood serum or byusing a nuclease resistance assay (e.g. snake venom phosphodiesterase(SVPD)), both are well known in the art. Internucleoside linkages whichare capable of enhancing the nuclease resistance of an oligonucleotideare referred to as nuclease resistant internucleoside linkages. In someembodiments at least 50% of the internucleoside linkages in theoligonucleotide, or contiguous nucleotide sequence thereof, aremodified, such as at least 60%, such as at least 70%, such as at least80 or such as at least 90% of the internucleoside linkages in theoligonucleotide, or contiguous nucleotide sequence thereof, are nucleaseresistant internucleoside linkages. In some embodiments all of theinternucleoside linkages of the oligonucleotide, or contiguousnucleotide sequence thereof, are nuclease resistant internucleosidelinkages. It will be recognized that, in some embodiments thenucleosides which link the oligonucleotide of the invention to anon-nucleotide functional group, such as a conjugate, may bephosphodiester.

A preferred modified internucleoside linkage is phosphorothioate.Phosphorothioate internucleoside linkages are particularly useful due tonuclease resistance, beneficial pharmacokinetics and ease ofmanufacture. In some embodiments at least 50% of the internucleosidelinkages in the oligonucleotide, or contiguous nucleotide sequencethereof, are phosphorothioate, such as at least 60%, such as at least70%, such as at least 80% or such as at least 90% of the internucleosidelinkages in the oligonucleotide, or contiguous nucleotide sequencethereof, are phosphorothioate. In some embodiments all of theinternucleoside linkages of the oligonucleotide, or contiguousnucleotide sequence thereof, are phosphorothioate.

Nuclease resistant linkages, such as phosphorothioate linkages, areparticularly useful in oligonucleotide regions capable of recruitingnuclease when forming a duplex with the target nucleic acid, such asregion G for gapmers. Phosphorothioate linkages may, however, also beuseful in non-nuclease recruiting regions and/or affinity enhancingregions such as regions F and F′ for gapmers. Gapmer oligonucleotidesmay, in some embodiments comprise one or more phosphodiester linkages inregion F or F′, or both region F and F′, which the internucleosidelinkage in region G may be fully phosphorothioate.

Advantageously, all the internucleoside linkages in the contiguousnucleotide sequence of the oligonucleotide are phosphorothioatelinkages.

It is recognized that, as disclosed in EP2 742 135, antisenseoligonucleotide may comprise other internucleoside linkages (other thanphosphodiester and phosphorothioate), for example alkylphosphonate/methyl phosphonate internucleosides, which according to EP2742 135 may for example be tolerated in an otherwise DNAphosphorothioate gap region.

As used herein, “phosphorothioate linkages” refer to internucleosidephosphate linkages where one of the non-bridging oxygens has beensubstituted with a sulfur. The substitution of one of the non-bridgingoxygens with a sulfur introduces a chiral center, and as such within asingle phosphorothioate oligonucleotide, each phosphorothioateinternucleoside linkage will be either in the S (Sp) or R (Rp)stereoisoforms. Such internucleoside linkages are referred to as “chiralinternucleoside linkages”. By comparison, phosphodiester internucleosidelinkages are non-chiral as they have two non-terminal oxygen atoms.

The designation of the chirality of a stereocenter is determined bystandard Cahn-Ingold-Prelog rules (CIP priority rules) first publishedin Cahn, R.S.; Ingold, C.K.; Prelog, V. (1966). “Specification ofMolecular Chirality”. Angewandte Chemie International Edition. 5 (4):385-415. doi:10.1002/anie.196603851.

During standard oligonucleotide synthesis, the stereoselectivity of thecoupling and the following sulfurization is not controlled. For thisreason, when producing an oligonucleotide by standard oligonucleotidesynthetic methods, the stereoconfiguration of any specificphosphorothioate internucleoside linkage introduced may become either Spor Rp. The resulting preparation of such an oligonucleotide maytherefore contain as many as 2^(X) different individual phosphorothioatediastereoisomers, where X is the number of phosphorothioateinternucleoside linkages. Such oligonucleotides are referred to as“stereorandom phosphorothioate oligonucleotides” herein, and do notcontain any stereodefined internucleoside linkages. Stereorandomphosphorothioate oligonucleotides are therefore mixtures of individualdiastereoisomers originating from the non-stereodefined synthesis. Inthis context the mixture is defined as up to 2′ differentphosphorothioate diastereoisomers. A stereorandom phosphorothioateinternucleoside linkage may also be referred to as a stereo-undefinedphosphorothioate internucleoside linkage or, using HELM-annotations,[sP] or (abbreviated) “X”, herein (see Examples 13 and 16).

As used herein, a “stereodefined internucleoside linkage” refers to aninternucleoside linkage which introduces a specific chiral center intothe oligonucleotide, which exists in predominantly one stereoisomericform, either R or S within a population of individual oligonucleotidemolecules.

It should be recognized that stereoselective oligonucleotide synthesismethods used in the art typically provide at least about 90% or at leastabout 95% stereoselectivity at each internucleoside linkagestereocenter, and as such up to about 10%, such as about 5% ofoligonucleotide molecules may have the alternative stereo isomeric form.

In some embodiments the stereoselectivity of each stereodefinedphosphorothioate stereocenter is at least about 90%. In some embodimentsthe stereoselectivity of each stereodefined phosphorothioatestereocenter is at least about 95%.

As used herein, “stereodefined phosphorothioate linkages” refer tophosphorothioate linkages which have been chemically synthesized ineither the Rp or Sp configuration within a population of individualoligonucleotide molecules, such as at least about 90% or at least about95% stereoselectivity at each stereocenter (either Rp or Sp), and assuch up to about 10%, such as about 5% of oligonucleotide molecules mayhave the alternative stereo isomeric form. The stereo configurations ofthe phosphorothioate internucleoside linkages are presented below

where the 3′ R group represents the 3′ position of the adjacentnucleoside (a 5′ nucleoside), and the 5′ R group represents the 5′position of the adjacent nucleoside (a 3′ nucleoside).

Rp internucleoside linkages may also be represented as srP, and Spinternucleoside linkages may be represented as ssP herein. Using HELMannotations, a stereodefined Sp phosphorothioate internucleoside linkagemay also be referred to as [ssP] or abbreviated as “S” herein (seeExamples 13 and 16).

In some embodiments the stereoselectivity of each stereodefinedphosphorothioate stereocenter is at least about 97%. In some embodimentsthe stereoselectivity of each stereodefined phosphorothioatestereocenter is at least about 98%. In some embodiments thestereoselectivity of each stereodefined phosphorothioate stereocenter isat least about 99%.

In some embodiments a stereoselective internucleoside linkage is in thesame stereoisomeric form in at least 97%, such as at least 98%, such asat least 99%, or (essentially) all of the oligonucleotide moleculespresent in a population of the oligonucleotide molecule.Stereoselectivity can be measured in a model system only having anachiral backbone (i.e. phosphodiesters) it is possible to measure thestereoselectivity of each monomer by e.g. coupling a stereodefinedmonomer to the following model-system “5′ t-po-t-po-t-po 3”. The resultof this will then give: 5′ DMTr-t-srp-t-po-t-po-t-po 3′ or 5′DMTr-t-ssp-t-po-t-po-t-po 3′ which can be separated using HPLC. Thestereoselectivity is determined by integrating the UV signal from thetwo possible compounds and giving a ratio of these e.g. 98:2, 99:1 or>99:1.

It will be understood that the stereo % purity of a specific singlediastereoisomer (a single stereodefined oligonucleotide molecule) willbe a function of the coupling selectivity for the defined stereocenterat each internucleoside position, and the number of stereodefinedinternucleoside linkages to be introduced. By way of example, if thecoupling selectivity at each position is 97%, the resulting purity ofthe stereodefined oligonucleotide with 15 stereodefined internucleosidelinkages will be 0.97¹⁵, i.e. 63% of the desired diastereoisomer ascompared to 37% of the other diastereoisomers. The purity of the defineddiastereoisomer may after synthesis be improved by purification, forexample by HPLC, such as ion exchange chromatography or reverse phasechromatography.

In some embodiments, a stereodefined oligonucleotide refers to apopulation of an oligonucleotide wherein at least about 40%, such as atleast about 50% of the population is of the desired diastereoisomer.

Alternatively stated, in some embodiments, a stereodefinedoligonucleotide refers to a population of oligonucleotides wherein atleast about 40%, such as at least about 50%, of the population consistsof the desired (specific) stereodefined internucleoside linkage motif(also termed stereodefined motif).

For stereodefined oligonucleotides which comprise both stereorandom andstereodefined internucleoside stereocenters, the purity of thestereodefined oligonucleotide is determined with reference to the % ofthe population of the oligonucleotide which retains the definedstereodefined internucleoside linkage motif(s), the stereorandomlinkages are disregarded in the calculation.

As used herein, a “stereodefined oligonucleotide” refers to anoligonucleotide wherein at least one of the internucleoside linkages isa stereodefined internucleoside linkage.

As used herein, a “stereodefined phosphorothioate oligonucleotide”refers to an oligonucleotide wherein at least one of the internucleosidelinkages is a stereodefined phosphorothioate internucleoside linkage.

As used herein, the term “complementarity” describes the capacity forWatson-Crick base-pairing of nucleosides/nucleotides. Watson-Crick basepairs are guanine (G)-cytosine (C) and adenine (A)-thymine (T)/uracil(U). It will be understood that oligonucleotides may comprisenucleosides with modified nucleobases, for example 5-methyl cytosine isoften used in place of cytosine, and as such the term complementarityencompasses Watson Crick base-paring between non-modified and modifiednucleobases (see for example Hirao et al (2012) Accounts of ChemicalResearch vol 45 page 2055 and Bergstrom (2009) Current Protocols inNucleic Acid Chemistry Suppl. 37 1.4.1).

As used herein, the term “% complementary” refers to the number ofnucleotides in percent of a contiguous nucleotide sequence in a nucleicacid molecule (e.g. oligonucleotide) which, at a given position, arecomplementary to (i.e. form Watson Crick base pairs with) a contiguoussequence of nucleotides, at a given position of a separate nucleic acidmolecule (e.g. the target nucleic acid or target sequence). Thepercentage is calculated by counting the number of aligned bases thatform pairs between the two sequences (when aligned with the targetsequence 5′-3′ and the oligonucleotide sequence from 3′-5′), dividing bythe total number of nucleotides in the oligonucleotide and multiplyingby 100. In such a comparison a nucleobase/nucleotide which does notalign (form a base pair) is termed a mismatch. Preferably, insertionsand deletions are not allowed in the calculation of % complementarity ofa contiguous nucleotide sequence.

As used herein, the term “fully complementary” refers to 100%complementarity.

As used herein, the term “identity” refers to the proportion ofnucleotides (expressed in percent) of a contiguous nucleotide sequencein a nucleic acid molecule (e.g. oligonucleotide) which across thecontiguous nucleotide sequence, are identical to a reference sequence(e.g. a sequence motif). The percentage of identity is thus calculatedby counting the number of aligned bases that are identical (a match)between two sequences (e.g. in the contiguous nucleotide sequence of thecompound of the invention and in the reference sequence), dividing thatnumber by the total number of nucleotides in the aligned region andmultiplying by 100. Therefore, Percentage ofIdentity=(Matches×100)/Length of aligned region (e.g. the contiguousnucleotide sequence). Insertions and deletions are not allowed in thecalculation the percentage of identity of a contiguous nucleotidesequence. It will be understood that in determining identity, chemicalmodifications of the nucleobases are disregarded as long as thefunctional capacity of the nucleobase to form Watson Crick base pairingis retained (e.g. 5-methyl cytosine is considered identical to acytosine for the purpose of calculating % identity).

As used herein, the term “hybridizing” or “hybridizes” refers to twonucleic acid strands (e.g. an oligonucleotide and a target nucleic acid)forming hydrogen bonds between base pairs on opposite strands therebyforming a duplex. The affinity of the binding between two nucleic acidstrands is the strength of the hybridization. It is often described interms of the melting temperature (T_(m)) defined as the temperature atwhich half of the oligonucleotides are duplexed with the target nucleicacid. At physiological conditions T_(m) is not strictly proportional tothe affinity (Mergny and Lacroix, 2003, Oligonucleotides 13:515-537).The standard state Gibbs free energy ΔG° is a more accuraterepresentation of binding affinity and is related to the dissociationconstant (K_(d)) of the reaction by ΔG°=−RTln(K_(d)), where R is the gasconstant and T is the absolute temperature. Therefore, a very low ΔG° ofthe reaction between an oligonucleotide and the target nucleic acidreflects a strong hybridization between the oligonucleotide and targetnucleic acid. ΔG° is the energy associated with a reaction where aqueousconcentrations are 1M, the pH is 7, and the temperature is 37° C. Thehybridization of oligonucleotides to a target nucleic acid is aspontaneous reaction and for spontaneous reactions ΔG° is less thanzero. ΔG° can be measured experimentally, for example, by use of theisothermal titration calorimetry (ITC) method as described in Hansen etal., 1965, Chem Comm. 36-38 and Holdgate et al., 2005, Drug DiscovToday. The skilled person will know that commercial equipment isavailable for ΔG° measurements. ΔG° can also be estimated numerically byusing the nearest neighbor model as described by SantaLucia, 1998, ProcNatl Acad Sci USA. 95: 1460-1465 using appropriately derivedthermodynamic parameters described by Sugimoto et al., 1995,Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry43:5388-5405. In order to have the possibility of modulating itsintended nucleic acid target by hybridization, oligonucleotides of thepresent invention hybridize to a target nucleic acid with estimated ΔG°values below −10 kcal for oligonucleotides that are 10-30 nucleotides inlength. In some embodiments the degree or strength of hybridization ismeasured by the standard state Gibbs free energy ΔG°. Theoligonucleotides may hybridize to a target nucleic acid with estimatedΔG° values below the range of −10 kcal, such as below −15 kcal, such asbelow −20 kcal and such as below −25 kcal for oligonucleotides that are8-30 nucleotides in length. In some embodiments the oligonucleotideshybridize to a target nucleic acid with an estimated ΔG° value of −10 to−60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27kcal such as −18 to −25 kcal.

As used herein, the term “target nucleic acid” refers to the nucleicacid which encodes a mammalian ATXN3 protein and may for example be agene, a ATXN3 RNA, a mRNA, a pre-mRNA, a mature mRNA or a cDNA sequence.The target may therefore be referred to as an “ATXN3 target nucleicacid”.

In some embodiments, the target nucleic acid encodes a human ATXN3protein, such as the human ATXN3 gene encoding the pre-mRNA sequenceprovided herein as SEQ ID NO:1. Thus, the target nucleic acid may be SEQID NO:1.

In some embodiments, the target nucleic acid encodes a mouse ATXN3protein. Suitably, the target nucleic acid encoding a mouse ATXN3protein comprises a sequence as shown in SEQ ID NO: 3.

In some embodiments, the target nucleic acid encodes a cynomolgus monkeyATXN3 protein. Suitably, the target nucleic acid encoding a cynomolgusmonkey ATXN3 protein comprises a sequence as shown in SEQ ID NO: 2.

If employing the oligonucleotide of the invention in research ordiagnostics the target nucleic acid may be a cDNA or a synthetic nucleicacid derived from DNA or RNA.

For in vivo or in vitro application, the oligonucleotide of theinvention is typically capable of inhibiting the expression of the ATXN3target nucleic acid in a cell which is expressing the ATXN3 targetnucleic acid. The contiguous sequence of nucleobases of theoligonucleotide of the invention is typically complementary to the ATXN3target nucleic acid, as measured across the length of theoligonucleotide, optionally with the exception of one or two mismatches,and optionally excluding nucleotide based linker regions which may linkthe oligonucleotide to an optional functional group such as a conjugate,or other non-complementary terminal nucleotides (e.g. region D′ or D″).The target nucleic acid is a messenger RNA, such as a mature mRNA or apre-mRNA which encodes mammalian ATXN3 protein, such as human ATXN3,e.g. the human ATXN3 pre-mRNA sequence, such as that disclosed as SEQ IDNO:1, or ATXN3 mature mRNA. Further, the target nucleic acid may be acynomolgus monkey ATXN3 pre-mRNA sequence, such as that disclosed as SEQID NO:1, or a cynomolgus monkey ATXN3 mature mRNA. Further, the targetnucleic acid may be a mouse ATXN3 pre-mRNA sequence, such as thatdisclosed as SEQ ID NO:3, or mouse ATXN3 mature mRNA. SEQ ID NOS:1-3 areDNA sequences it will be understood that target RNA sequences haveuracil (U) bases in place of the thymidine bases (T).

TABLE 1 Target nucleic acids Target Nucleic Acid Sequence ID ATXN3 Homosapien spre-mRNA SEQ ID NO: 1 ATXN3 Macaca fascicularis pre-mRNA SEQ IDNO: 2 ATXN3 Mus musculus mRNA SEQ ID NO: 3

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:1.

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:2.

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:3.

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:1 and SEQ ID NO:2.

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:1 and SEQ ID NO:3.

In some embodiments, the oligonucleotide of the invention targets SEQ IDNO:1, SEQ ID NO:2 and SEQ ID NO:3.

As used herein, the term “target sequence” refers to a sequence ofnucleotides present in the target nucleic acid which comprises thenucleobase sequence which is complementary to the oligonucleotide of theinvention. In some embodiments, the target sequence consists of a regionon the target nucleic acid which is complementary to the contiguousnucleotide sequence of the oligonucleotide of the invention.

Herein are provided numerous target sequence regions, as defined byregions of the human ATXN3 pre-mRNA (using SEQ ID NO:1 as a reference)which may be targeted by the oligonucleotides of the invention.

In some embodiments the target sequence is longer than the complementarysequence of a single oligonucleotide, and may, for example represent apreferred region of the target nucleic acid which may be targeted byseveral oligonucleotides of the invention.

The oligonucleotide of the invention comprises a contiguous nucleotidesequence which is complementary to or hybridizes to the target nucleicacid, such as a sub-sequence of the target nucleic acid, such as atarget sequence described herein.

The oligonucleotide comprises a contiguous nucleotide sequence which arecomplementary to a target sequence present in the target nucleic acidmolecule. The contiguous nucleotide sequence (and therefore the targetsequence) comprises at least 10 contiguous nucleotides, such as 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29 or 30 contiguous nucleotides, such as from 12-25, such as from 14-18contiguous nucleotides.

As used herein, the term “target sequence region” refers to an antisenseoligonucleotide, 10-30 nucleotides in length, wherein said antisenseoligonucleotide comprises a contiguous nucleotide sequence 10-30nucleotides in length, wherein the contiguous nucleotide sequence is atleast 90% complementary to a region of SEQ ID NO:1. The region of SEQ IDNO:1 to which the antisense oligonucleotide of the invention iscomplementary to is referred to as the target sequence region.

In some embodiments the target sequence region is AAGAGTAAAATATGGGT (SEQID NO:1093).

In some embodiments the target sequence region is GAATGTAAAAGTGTACAG(SEQ ID NO:1094).

In some embodiments the target sequence region is GGAATGTAAAAGTGTACA(SEQ ID NO:1095).

In some embodiments the target sequence region is GGGAATGTAAAAGTGTAC(SEQ ID NO:1096).

In some embodiments the target sequence region is TTGATGGTATAATGAAGAA(SEQ ID NO:1097).

In some embodiments the target sequence region is GGAAGATGTAAATAAGATT(SEQ ID NO:1098).

In some embodiments, the target sequence region is AAGATGTAAATAAGATTC(SEQ ID NO:1992).

It is to be understood that target RNA sequences have uracil (U) basesin place of any thymidine (T) bases.

As used herein, the term “off-target sequence” refers to a sequence ofnucleotides comprising a nucleobase sequence which may be partiallycomplementary to an oligonucleotide of the invention but which ispresent in another nucleic acid than the target (ATXN3) nucleic acid.

As used herein, the term “target cell” refers to a cell which isexpressing the target nucleic acid. In some embodiments the target cellmay be in vivo or in vitro. In some embodiments the target cell is amammalian cell such as a rodent cell, such as a mouse cell or a ratcell, or a primate cell such as a monkey cell (e.g. a cynomolgus monkeycell) or a human cell.

In preferred embodiments the target cell expresses human ATXN3 mRNA,such as the ATXN3 pre-mRNA, e.g. SEQ ID NO:1, or ATXN3 mature mRNA. Insome embodiments the target cell expresses monkey ATXN3 mRNA, such asthe ATXN3 pre-mRNA, e.g. SEQ ID NO:2, or ATXN3 mature mRNA. In someembodiments the target cell expresses mouse ATXN3 mRNA, such as theATXN3 pre-mRNA, e.g. SEQ ID NO:3, or ATXN3 mature mRNA. The poly A tailof ATXN3 mRNA is typically disregarded for antisense oligonucleotidetargeting.

As used herein, the term “naturally occurring variant” refers tovariants of ATXN3 gene or transcripts which originate from the samegenetic loci as the target nucleic acid, but may differ for example, byvirtue of degeneracy of the genetic code causing a multiplicity ofcodons encoding the same amino acid, or due to alternative splicing ofpre-mRNA, or the presence of polymorphisms, such as single nucleotidepolymorphisms (SNPs), and allelic variants. Based on the presence of thesufficient complementary sequence to the oligonucleotide, theoligonucleotide of the invention may therefore target the target nucleicacid and naturally occurring variants thereof.

The Homo sapiens ATXN3 gene is located at chromosome 14,92058552..92106621, complement (NC 000014.9, Gene ID 4287).

In some embodiments, the naturally occurring variants have at least 95%such as at least 98% or at least 99% homology to a mammalian ATXN3target nucleic acid, such as a target nucleic acid selected form thegroup consisting of SEQ ID NOS:1, 2 and 3. In some embodiments thenaturally occurring variants have at least 99% homology to the humanATXN3 target nucleic acid of SEQ ID NO:1.

As used herein, the term “modulation of expression” refers to an overallterm for an oligonucleotide's ability to alter the amount of ATXN3protein or ATXN3 mRNA when compared to the amount of ATXN3 or ATXN3 mRNAprior to administration of the oligonucleotide. Alternatively modulationof expression may be determined by reference to a control experiment. Itis generally understood that the control is an individual or target celltreated with a saline composition or an individual or target celltreated with a non-targeting oligonucleotide (mock).

One type of modulation is an oligonucleotide's ability to inhibit,down-regulate, reduce, suppress, remove, stop, block, prevent, lessen,lower, avoid or terminate expression of ATXN3, e.g. by degradation ofATXN3 mRNA.

As used herein, a “high affinity modified nucleoside” refers to amodified nucleoside which, when incorporated into the oligonucleotideenhances the affinity of the oligonucleotide for its complementarytarget, for example as measured by the melting temperature (T_(m)). Ahigh affinity modified nucleoside of the present invention preferablyresult in an increase in melting temperature between +0.5 to +12° C.,more preferably between +1.5 to +10° C. and most preferably between +3to +8° C. per modified nucleoside. Numerous high affinity modifiednucleosides are known in the art and include for example, many 2′substituted nucleosides as well as locked nucleic acids (LNA) (see e.g.Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann;Curr. Opinion in Drug Development, 2000, 3(2), 293-213).

As used herein, the term “RNase H activity” refers to the ability of anantisense oligonucleotide to recruit RNase H when in a duplex with acomplementary RNA molecule. WO 01/23613 provides in vitro methods fordetermining RNaseH activity, which may be used to determine the abilityto recruit RNaseH. Typically an oligonucleotide is deemed capable ofrecruiting RNase H if it, when provided with a complementary targetnucleic acid sequence, has an initial rate, as measured in pmol/l/min,of at least 5%, such as at least 10% or more than 20% of the of theinitial rate determined when using a oligonucleotide having the samebase sequence as the modified oligonucleotide being tested, butcontaining only DNA monomers with phosphorothioate linkages between allmonomers in the oligonucleotide, and using the methodology provided byExample 91-95 of WO01/23613 (hereby incorporated by reference). For usein determining RHase H activity, recombinant human RNase H1 is availablefrom Lubio Science GmbH, Lucerne, Switzerland.

The antisense oligonucleotide of the invention, or contiguous nucleotidesequence thereof may be a gapmer. The antisense gapmers are commonlyused to inhibit a target nucleic acid via RNase H mediated degradation.

As used herein, the term “gapmer oligonucleotide” refers to anoligonucleotide that comprises at least three distinct structuralregions—a 5′-flank, a gap and a 3′-flank (F-G-F′)- in the ‘5→3’orientation. The “gap” region (G) comprises a stretch of contiguous DNAnucleotides which enable the oligonucleotide to recruit RNase H. The gapregion is flanked by a 5′ flanking region (F) comprising one or moresugar modified nucleosides, advantageously high affinity sugar modifiednucleosides, and by a 3′ flanking region (F′) comprising one or moresugar modified nucleosides, advantageously high affinity sugar modifiednucleosides. The one or more sugar modified nucleosides in region F andF′ enhance the affinity of the oligonucleotide for the target nucleicacid (i.e. are affinity enhancing sugar modified nucleosides). In someembodiments, the one or more sugar modified nucleosides in region F andF′ are 2′ sugar modified nucleosides, such as high affinity 2′ sugarmodifications, such as independently selected from LNA and 2′-MOE.

In a gapmer design, the 5′ and 3′ most nucleosides of the gap region areDNA nucleosides, and are positioned adjacent to a sugar modifiednucleoside of the 5′ (F) or 3′ (F′) region respectively. The flanks mayfurther defined by having at least one sugar modified nucleoside at theend most distant from the gap region, i.e. at the 5′ end of the 5′ flankand at the 3′ end of the 3′ flank.

Regions F-G-F′ form a contiguous nucleotide sequence. Antisenseoligonucleotides of the invention, or the contiguous nucleotide sequencethereof, may comprise a gapmer region of formula F-G-F′.

The overall length of the gapmer design F-G-F′ may be, for example 12 to32 nucleosides, such as 13 to 24, such as 14 to 22 nucleosides, Such asfrom 14 to 17, such as 16 to 18 nucleosides.

By way of example, the gapmer oligonucleotide of the present inventioncan be represented by the following formulae:

F₁₋₈-G₅₋₁₆-F′₁₋₈, such as

F₁₋₈-G₇₋₁₆-F′₂₋₈

with the proviso that the overall length of the gapmer regions F-G-F′ isat least 12, such as at least 14 nucleotides in length.

Regions F, G and F′ are further defined below and can be incorporatedinto the F-G-F′ formula.

As used herein, “region G (gap region)” of the gapmer refers to a regionof nucleosides which enables the oligonucleotide to recruit RNaseH, suchas human RNase H1, typically DNA nucleosides. RNaseH is a cellularenzyme which recognizes the duplex between DNA and RNA, andenzymatically cleaves the RNA molecule. Suitably gapmers may have a gapregion (G) of at least 5 or 6 contiguous DNA nucleosides, such as 5-16contiguous DNA nucleosides, such as 6-15 contiguous DNA nucleosides,such as 7-14 contiguous DNA nucleosides, such as 8-12 contiguous DNAnucleotides, such as 8-12 contiguous DNA nucleotides in length. The gapregion G may, in some embodiments consist of 6, 7, 8, 9, 10, 11, 12, 13,14, 15 or 16 contiguous DNA nucleosides. One or more cytosine (C) DNA inthe gap region may in some instances be methylated (e.g. when a DNA c isfollowed by a DNA g) such residues are either annotated as5-methyl-cytosine (^(me)C). In some embodiments the gap region G mayconsist of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 contiguousphosphorothioate linked DNA nucleosides. In some embodiments, allinternucleoside linkages in the gap are phosphorothioate linkages.Whilst traditional gapmers have a DNA gap region, there are numerousexamples of modified nucleosides which allow for RNaseH recruitment whenthey are used within the gap region. Modified nucleosides which havebeen reported as being capable of recruiting RNaseH when included withina gap region include, for example, alpha-L-LNA, C4′ alkylated DNA (asdescribed in PCT/EP2009/050349 and Vester et al., Bioorg. Med. Chem.Lett. 18 (2008) 2296-2300, both incorporated herein by reference),arabinose derived nucleosides like ANA and 2′F-ANA (Mangos et al. 2003J. AM. CHEM. SOC. 125, 654-661), UNA (unlocked nucleic acid) (asdescribed in Fluiter et al., Mol. Biosyst., 2009, 10, 1039 incorporatedherein by reference). UNA is unlocked nucleic acid, typically where thebond between C2 and C3 of the ribose has been removed, forming anunlocked “sugar” residue. The modified nucleosides used in such gapmersmay be nucleosides which adopt a 2′ endo (DNA like) structure whenintroduced into the gap region, i.e. modifications which allow forRNaseH recruitment). In some embodiments the DNA Gap region (G)described herein may optionally contain 1 to 3 sugar modifiednucleosides which adopt a 2′ endo (DNA like) structure when introducedinto the gap region.

Alternatively, there are numerous reports of the insertion of a modifiednucleoside which confers a 3′ endo conformation into the gap region ofgapmers, whilst retaining some RNaseH activity. Such gapmers with a gapregion comprising one or more 3′ endo modified nucleosides are referredto as “gap-breaker” or “gap-disrupted” gapmers, see for exampleWO2013/022984.

As used herein, the term “gap-breaker” or “gap-disrupted” refers tooligonucleotides that retain sufficient region of DNA nucleosides withinthe gap region to allow for RNaseH recruitment. The ability of“gap-breaker” oligonucleotide design to recruit RNaseH is typicallysequence or even compound specific see Rukov et al. 2015 Nucl. AcidsRes. Vol. 43 pp. 8476-8487, which discloses “gap-breaker”oligonucleotides which recruit RNaseH which in some instances provide amore specific cleavage of the target RNA. Modified nucleosides usedwithin the gap region of gap-breaker oligonucleotides may for example bemodified nucleosides which confer a 3′ endo confirmation, such 2′O-methyl (OMe) or 2′-O-MOE (MOE) nucleosides, or beta-D LNA nucleosides(the bridge between C2′ and C4′ of the ribose sugar ring of a nucleosideis in the beta conformation), such as beta-D-oxy LNA or ScETnucleosides.

As with gapmers containing region G described above, the gap region of“gap-breaker” or “gap-disrupted” gapmers, have a DNA nucleosides at the5′ end of the gap (adjacent to the 3′ nucleoside of region F), and a DNAnucleoside at the 3′ end of the gap (adjacent to the 5′ nucleoside ofregion F′). Gapmers which comprise a disrupted gap typically retain aregion of at least 3 or 4 contiguous DNA nucleosides at either the 5′end or 3′ end of the gap region.

Exemplary designs for gap-breaker oligonucleotides include:

F₁₋₈-[D₃₋₄-E₁-D₃₋₄]-F′₁₋₈

F₁₋₈-[D₁₋₄-E₁-D₃₋₄]-F′₁₋₈

F₁₋₈-[D₃₋₄-E₁-D₁₋₄]-F′₁₋₈

wherein region G is within the brackets [D_(n)-E_(r)-D_(m)], D is acontiguous sequence of DNA nucleosides, E is a modified nucleoside (thegap-breaker or gap-disrupting nucleoside), and F and F′ are the flankingregions as defined herein, and with the proviso that the overall lengthof the gapmer regions F-G-F′ is at least 12, such as at least 14nucleotides in length.

In some embodiments, region G of a gap disrupted gapmer comprises atleast 6 DNA nucleosides, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or16 DNA nucleosides. As described above, the DNA nucleosides may becontiguous or may optionally be interspersed with one or more modifiednucleosides, with the proviso that the gap region G is capable ofmediating RNaseH recruitment.

As used herein, “region F (flanking region)” of the gapmer refers to aregion of nucleosides that is positioned immediately adjacent to the 5′DNA nucleoside of region G. The 3′ most nucleoside of region F is asugar modified nucleoside, such as a high affinity sugar modifiednucleoside, for example a 2′ substituted nucleoside, such as a MOEnucleoside, or an LNA nucleoside.

As used herein, “region F′ (flanking region)” of the gapmer refers to aregion of nucleosides that is positioned immediately adjacent to the 3′DNA nucleoside of region G. The 5′ most nucleoside of region F′ is asugar modified nucleoside, such as a high affinity sugar modifiednucleoside, for example a 2′ substituted nucleoside, such as a MOEnucleoside, or an LNA nucleoside.

Region F is 1-8 contiguous nucleotides in length, such as 2-6, such as3-4 contiguous nucleotides in length. Advantageously the 5′ mostnucleoside of region F is a sugar modified nucleoside. In someembodiments the two 5′ most nucleoside of region F are sugar modifiednucleoside. In some embodiments the 5′ most nucleoside of region F is anLNA nucleoside. In some embodiments the two 5′ most nucleoside of regionF are LNA nucleosides. In some embodiments the two 5′ most nucleoside ofregion F are 2′ substituted nucleoside nucleosides, such as two 3′ MOEnucleosides. In some embodiments the 5′ most nucleoside of region F is a2′ substituted nucleoside, such as a MOE nucleoside.

Region F′ is 2-8 contiguous nucleotides in length, such as 3-6, such as4-5 contiguous nucleotides in length. Advantageously, embodiments the 3′most nucleoside of region F′ is a sugar modified nucleoside. In someembodiments the two 3′ most nucleoside of region F′ are sugar modifiednucleoside. In some embodiments the two 3′ most nucleoside of region F′are LNA nucleosides. In some embodiments the 3′ most nucleoside ofregion F′ is an LNA nucleoside. In some embodiments the two 3′ mostnucleoside of region F′ are 2′ substituted nucleoside nucleosides, suchas two 3′ MOE nucleosides. In some embodiments the 3′ most nucleoside ofregion F′ is a 2′ substituted nucleoside, such as a MOE nucleoside.

It should be noted that when the length of region F or F′ is one, it isadvantageously an LNA nucleoside.

In some embodiments, region F and F′ independently consists of orcomprises a contiguous sequence of sugar modified nucleosides. In someembodiments, the sugar modified nucleosides of region F may beindependently selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA,2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNAunits, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.

In some embodiments, region F and F′ independently comprises both LNAand a 2′ substituted modified nucleosides (mixed wing design).

In some embodiments, region F and F′ consists of only one type of sugarmodified nucleosides, such as only MOE or only beta-D-oxy LNA or onlyScET. Such designs are also termed uniform flanks or uniform gapmerdesign.

In some embodiments, all the nucleosides of region F or F′, or F and F′are LNA nucleosides, such as independently selected from beta-D-oxy LNA,ENA or ScET nucleosides.

In some embodiments, all the nucleosides of region F or F′, or F and F′are 2′ substituted nucleosides, such as OMe or MOE nucleosides. In someembodiments region F consists of 1, 2, 3, 4, 5, 6, 7, or 8 contiguousOMe or MOE nucleosides. In some embodiments only one of the flankingregions can consist of 2′ substituted nucleosides, such as OMe or MOEnucleosides. In some embodiments it is the 5′ (F) flanking region thatconsists 2′ substituted nucleosides, such as OMe or MOE nucleosideswhereas the 3′ (F′) flanking region comprises at least one LNAnucleoside, such as beta-D-oxy LNA nucleosides or cET nucleosides. Insome embodiments it is the 3′ (F′) flanking region that consists 2′substituted nucleosides, such as OMe or MOE nucleosides whereas the 5′(F) flanking region comprises at least one LNA nucleoside, such asbeta-D-oxy LNA nucleosides or cET nucleosides.

In some embodiments, all the modified nucleosides of region F and F′ areLNA nucleosides, such as independently selected from beta-D-oxy LNA, ENAor ScET nucleosides, wherein region F or F′, or F and F′ may optionallycomprise DNA nucleosides (an alternating flank, see definition of thesefor more details). In some embodiments, all the modified nucleosides ofregion F and F′ are beta-D-oxy LNA nucleosides, wherein region F or F′,or F and F′ may optionally comprise DNA nucleosides (an alternatingflank, see definition of these for more details).

In some embodiments the 5′ most and the 3′ most nucleosides of region Fand F′ are LNA nucleosides, such as beta-D-oxy LNA nucleosides or ScETnucleosides.

In some embodiments, the internucleoside linkage between region F andregion G is a phosphorothioate internucleoside linkage. In someembodiments, the internucleoside linkage between region F′ and region Gis a phosphorothioate internucleoside linkage. In some embodiments, theinternucleoside linkages between the nucleosides of region F or F′, Fand F′ are phosphorothioate internucleoside linkages.

As used herein, the term “LNA gapmer” refers to a gapmer wherein eitherone or both of region F and F′ comprises or consists of LNA nucleosides.A beta-D-oxy gapmer is a gapmer wherein either one or both of region Fand F′ comprises or consists of beta-D-oxy LNA nucleosides.

In some embodiments the LNA gapmer is of formula: [LNA]₁₋₅-[regionG]-[LNA]₁₋₅, wherein region G is as defined in the Gapmer region Gdefinition.

As used herein, the term “MOE gapmer” refers to a gapmer wherein regionsF and F′ consist of MOE nucleosides. In some embodiments the MOE gapmeris of design [MOE]₁₋₈-[Region G]-[MOE]₁₋₈, such as [MOE]₂₋₇-[RegionG]₅₋₁₆-[MOE]₂₋₇, such as [MOE]₃₋₆-[Region G]-[MOE]₃₋₆, wherein region Gis as defined in the Gapmer definition. MOE gapmers with a 5-10-5 design(MOE-DNA-MOE) have been widely used in the art.

As used herein, the term “mixed wing gapmer” refers to an LNA gapmerwherein one or both of region F and F′ comprise a 2′ substitutednucleoside, such as a 2′ substituted nucleoside independently selectedfrom the group consisting of 2′-O-alkyl-RNA units, 2′-O-methyl-RNA,2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units,arabino nucleic acid (ANA) units and 2′-fluoro-ANA units, such as a MOEnucleosides. In some embodiments wherein at least one of region F andF′, or both region F and F′ comprise at least one LNA nucleoside, theremaining nucleosides of region F and F′ are independently selected fromthe group consisting of MOE and LNA. In some embodiments wherein atleast one of region F and F′, or both region F and F′ comprise at leasttwo LNA nucleosides, the remaining nucleosides of region F and F′ areindependently selected from the group consisting of MOE and LNA. In somemixed wing embodiments, one or both of region F and F′ may furthercomprise one or more DNA nucleosides.

Mixed wing gapmer designs are disclosed in WO2008/049085 andWO2012/109395, both of which are hereby incorporated by reference.

As used herein, the term “Alternating Flank Gapmer” refers to LNA gapmeroligonucleotides where at least one of the flanks (F or F′) comprisesDNA in addition to the LNA nucleoside(s). In some embodiments at leastone of region F or F′, or both region F and F′, comprise both LNAnucleosides and DNA nucleosides. In such embodiments, the flankingregion F or F′, or both F and F′ comprise at least three nucleosides,wherein the 5′ and 3′ most nucleosides of the F and/or F′ region are LNAnucleosides.

In some embodiments at least one of region F or F′, or both region F andF′, comprise both LNA nucleosides and DNA nucleosides. In suchembodiments, the flanking region F or F′, or both F and F′ comprise atleast three nucleosides, wherein the 5′ and 3′ most nucleosides of the For F′ region are LNA nucleosides, and there is at least one DNAnucleoside positioned between the 5′ and 3′ most LNA nucleosides ofregion F or F′ (or both region F and F′).

The oligonucleotide of the invention may in some embodiments comprise orconsist of the contiguous nucleotide sequence of the oligonucleotidewhich is complementary to the target nucleic acid, such as the gapmerF-G-F′, and further 5′ and/or 3′ nucleosides. The further 5′ and/or 3′nucleosides may or may not be fully complementary to the target nucleicacid. Such further 5′ and/or 3′ nucleosides may be referred to as“region D′” and “region D″” herein.

The addition of “region D′” or “region D″” may be used for the purposeof joining the contiguous nucleotide sequence, such as the gapmer, to aconjugate moiety or another functional group. When used for joining thecontiguous nucleotide sequence with a conjugate moiety is can serve as abiocleavable linker. Alternatively it may be used to provide exonucleaseprotection or for ease of synthesis or manufacture.

“Region D′” and “Region D″” can be attached to the 5′ end of region F orthe 3′ end of region F′, respectively to generate designs of thefollowing formulas D′-F-G-F′, F-G-F′-D″ or D′-F-G-F′-D″. In thisinstance the F-G-F′ is the gapmer portion of the oligonucleotide andregion D′ or D″ constitute a separate part of the oligonucleotide.

“Region D′” or “Region D″” may independently comprise or consist of 1,2, 3, 4 or 5 additional nucleotides, which may be complementary ornon-complementary to the target nucleic acid. The nucleotide adjacent tothe F or F′ region is not a sugar-modified nucleotide, such as a DNA orRNA or base modified versions of these. The D′ or D′ region may serve asa nuclease susceptible biocleavable linker (see definition of linkers).In some embodiments the additional 5′ and/or 3′ end nucleotides arelinked with phosphodiester linkages, and are DNA or RNA. Nucleotidebased biocleavable linkers suitable for use as region D′ or D″ aredisclosed in WO2014/076195, which include by way of example aphosphodiester linked DNA dinucleotide. The use of biocleavable linkersin poly-oligonucleotide constructs is disclosed in WO2015/113922, wherethey are used to link multiple antisense constructs (e.g. gapmerregions) within a single oligonucleotide.

In one embodiment the oligonucleotide of the invention comprises aregion D′ and/or D″ in addition to the contiguous nucleotide sequencewhich constitutes the gapmer.

In some embodiments, the oligonucleotide of the present invention can berepresented by the following formulae:

F-G-F′; in particular F₁₋₈-G₅₋₁₆-F′₂₋₈

D′-F-G-F′, in particular D′₁₋₃-F₁₋₈-G₅₋₁₆-F′₂₋₈

F-G-F′-D″, in particular F₁₋₈-G₅₋₁₆-F′₂₋₈-D″₁₋₃

D′-F-G-F′-D″, in particular D′₁₋₃-F₁₋₈-G₅₋₁₆-F₂₋₈-D″₁₋₃

In some embodiments the internucleoside linkage positioned betweenregion D′ and region F is a phosphodiester linkage. In some embodimentsthe internucleoside linkage positioned between region F′ and region D″is a phosphodiester linkage.

As used herein, the term “conjugate” refers to an oligonucleotide whichis covalently linked to a non-nucleotide moiety (conjugate moiety orregion C or third region).

Conjugation of the oligonucleotide of the invention to one or morenon-nucleotide moieties may improve the pharmacology of theoligonucleotide, e.g. by affecting the activity, cellular distribution,cellular uptake or stability of the oligonucleotide. In some embodimentsthe conjugate moiety modify or enhance the pharmacokinetic properties ofthe oligonucleotide by improving cellular distribution, bioavailability,metabolism, excretion, permeability, and/or cellular uptake of theoligonucleotide. In particular the conjugate may target theoligonucleotide to a specific organ, tissue or cell type and therebyenhance the effectiveness of the oligonucleotide in that organ, tissueor cell type. At the same time the conjugate may serve to reduceactivity of the oligonucleotide in non-target cell types, tissues ororgans, e.g. off target activity or activity in non-target cell types,tissues or organs.

In an embodiment, the non-nucleotide moiety (conjugate moiety) isselected from the group consisting of carbohydrates, cell surfacereceptor ligands, drug substances, hormones, lipophilic substances,polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins,viral proteins (e.g. capsids) or combinations thereof.

As used herein, the term “linkage” or “linker” refers to a connectionbetween two atoms that links one chemical group or segment of interestto another chemical group or segment of interest via one or morecovalent bonds. Conjugate moieties can be attached to theoligonucleotide directly or through a linking moiety (e.g. linker ortether). Linkers serve to covalently connect a third region, e.g. aconjugate moiety (Region C), to a first region, e.g. an oligonucleotideor contiguous nucleotide sequence or gapmer region F-G-F′ (region A).

In some embodiments of the invention the conjugate or oligonucleotideconjugate of the invention may optionally, comprise a linker region(second region or region B and/or region Y) which is positioned betweenthe oligonucleotide or contiguous nucleotide sequence complementary tothe target nucleic acid (region A or first region) and the conjugatemoiety (region C or third region).

As used herein, the term “Region B” refers to biocleavable linkerscomprising or consisting of a physiologically labile bond that iscleavable under conditions normally encountered or analogous to thoseencountered within a mammalian body. Conditions under whichphysiologically labile linkers undergo chemical transformation (e.g.,cleavage) include chemical conditions such as pH, temperature, oxidativeor reductive conditions or agents, and salt concentration found in oranalogous to those encountered in mammalian cells. Mammalianintracellular conditions also include the presence of enzymatic activitynormally present in a mammalian cell such as from proteolytic enzymes orhydrolytic enzymes or nucleases. In one embodiment the biocleavablelinker is susceptible to Si nuclease cleavage. DNA phosphodiestercontaining biocleavable linkers are described in more detail in WO2014/076195 (hereby incorporated by reference) see also region D′ or D″herein.

As used herein, the term “Region Y” refers to linkers that are notnecessarily biocleavable but primarily serve to covalently connect aconjugate moiety (region C or third region), to an oligonucleotide(region A or first region). The region Y linkers may comprise a chainstructure or an oligomer of repeating units such as ethylene glycol,amino acid units or amino alkyl groups. The oligonucleotide conjugatesof the present invention can be constructed of the following regionalelements A-C, A-B-C, A-B—Y—C, A-Y—B—C or A-Y-C. In some embodiments thelinker (region Y) is an amino alkyl, such as a C2 to C36 amino alkylgroup, including, for example C6 to C12 amino alkyl groups. In apreferred embodiment the linker (region Y) is a C6 amino alkyl group.

II. Oligonucleotides for Inhibiting ATXN3

The invention relates to oligonucleotides, such as antisenseoligonucleotides, targeting ATXN3 expression.

The oligonucleotides of the invention targeting ATXN3 are capable ofhybridizing to and inhibiting the expression of a ATXN3 target nucleicacid in a cell which is expressing the ATXN3 target nucleic acid.

The ATXN3 target nucleic acid may be a mammalian ATXN3 mRNA or premRNA,such as a human, mouse or monkey ATXN3 mRNA or premRNA. In someembodiments, the ATXN3 target nucleic acid is ATXN3 mRNA or premRNA forexample a premRNA or mRNA originating from the Homo sapiens Ataxin 3(ATXN3), RefSeqGene on chromosome 14, exemplified by NCBI ReferenceSequence NM 004993.5 (SEQ ID NO:1).

The human ATXN3 pre-mRNA is encoded on Homo sapiens Chromosome 14, NC000014.9 (92058552..92106621, complement). GENE ID=4287 (ATXN3).

The oligonucleotides of the invention are capable of inhibiting theexpression of ATXN3 target nucleic acid, such as the ATXN3 mRNA, in acell which is expressing the target nucleic acid, such as the ATXN3 mRNA(e.g. a human, monkey or mouse cell).

In some embodiments, the oligonucleotides of the invention are capableof inhibiting the expression of ATXN3 target nucleic acid in a cellwhich is expressing the target nucleic acid, so to reduce the level ofATXN3 target nucleic acid (e.g. the mRNA) by at least 50%, at least 60%,at least 70%, at least 80%, or at least 90% inhibition compared to theexpression level of the ATXN3 target nucleic acid (e.g. the mRNA) in thecell. Suitably the cell is selected from the group consisting of a humancell, a monkey cell and a mouse cell. In some embodiments, the cell is aSK-N-AS, A431, NCI-H23 or ARPE19 cell (for more information on thesecells, see Examples). Example 1 provides a suitable assay for evaluatingthe ability of the oligonucleotides of the invention to inhibit theexpression of the target nucleic acid. Suitably the evaluation of acompounds ability to inhibit the expression of the target nucleic acidis performed in vitro, such a gymnotic in vitro assay, for example asaccording to Example 1.

In some embodiments, an oligonucleotide of the invention is more capablein inhibiting the expression of ATXN3 target nucleic acid in a cellwhich is expressing the target nucleic acid than in inhibiting theexpression of KCNB2 nucleic acid in a cell which is expressing the KCNB2nucleic acid, providing for a higher selectivity in targeting the ATXN3target nucleic acid. KCNB2 (Potassium Voltage-Gated Channel Subfamily BMember 2) nucleic acid was identified as containing a potentialoff-target sequence which may be annealed to certain oligonucleotidestargeting SEQ ID NO:1098 and/or SEQ ID NO:1992. Information, includingsequence information, about the KCNB2 gene and transcripts can be foundin the public database Ensembl (release 101) at gene id ENSG00000182674.

Suitably, the capability of an oligonucleotide to inhibit the expressionof ATXN3 and KCNB2 nucleic acids is tested in a cell expressing bothnucleic acids. In some embodiments, an oligonucleotide of the inventionis capable of inhibiting the expression of ATXN3 target nucleic acid soas to reduce the level of ATXN3 target nucleic acid (e.g. the mRNA) by afraction which is at least 50%, at least 60%, at least 70%, at least80%, or at least 90% inhibition compared to the expression level of theATXN3 target nucleic acid (e.g. the mRNA) in the cell, but reduces thelevel of KCNB2 off-target nucleic acid (e.g., the mRNA) as compared tothe expression level of the KCNB2 target nucleic acid (e.g. the mRNA) inthe cell by a smaller fraction. The cell, may, for example, be selectedfrom the group consisting of a human cell, a monkey cell and a mousecell. In some embodiments, the cell is a neuronal cell, such as aniCell® Glutaneuron cell (for more information on these cells, see Table2). Examples 5 and 14 provides suitable assays for evaluating theability of the oligonucleotides of the invention to inhibit theexpression of the target nucleic acid as compared to the off-targetnucleic acid. Suitably the evaluation of the ability of anoligonucleotide to inhibit the expression of the target nucleic acid andthe off-target nucleic acid is performed in vitro, such a gymnotic invitro assay, for example as according to Example 14.

Advantageously, an oligonucleotide according to the invention has a lowEC50 in inhibiting the expression of ATXN3 target nucleic acid in a cellwhich is expressing the target nucleic acid, providing for a highefficacy and/or potency in targeting the ATXN3 target nucleic acid. Insome embodiments, the EC50 for inhibiting the expression of ATXN3 targetnucleic acid is no more than about 1 μM, such as no more than about 500nM, such as no more than about 300 nM, such as no more than about 200nM, such as no more than about 180 nM, such as no more than about 170nM, such as no more than about 160 nM, such as no more than about 150nM, such as no more than about 140 nM, such as no more than about 130nM, such as no more than about 120 nM, such as no more than about 110nM, such as no more than about 100 nM, such as no more than about 90 nM,such as no more than about 80 nM, such as no more than about 70 nM, suchas no more than about 60 nM, such as no more than about 50 nM. The cell,may, for example, be selected from the group consisting of a human cell,a monkey cell and a mouse cell. In some embodiments, the cell is aneuronal cell, such as a human neuronal cell, such as an iCell®GlutaNeuron cell (for more information on these cells, see Table 2). Aparticularly suitable assay is described in Example 16.

Preferably, an oligonucleotide according to the invention also oralternatively has a lower EC50 for inhibiting the expression of ATXN3target nucleic acid (e.g., mRNA) in a cell than for inhibiting theexpression of KCNB2 off-target nucleic acid (e.g., mRNA) in the cell,indicating that 50% inhibition of the expression of the nucleic acid is,for ATXN3 target nucleic acid, achieved at a lower oligonucleotideconcentration, thereby providing for a higher selectivity. In someembodiments, the ratio between the EC50 for inhibiting the expression ofKCNB2 off-target nucleic acid (e.g., mRNA) and the EC50 for inhibitingthe expression of ATXN3 target nucleic acid is at least about 2, such asat least about 2.1, such as at least about 2.2, such as at least about2.5, such as at least about 3, such as at least about 4, such as atleast about 5, such as at least about 6, such as at least about 7, suchas at least about 8, such as at least about 9, such as at least about10, such as at least about 12, such as at least about 15, such as atleast about 20, such as at least about 50, such as at least about 100,such as at least about 200, such as at least about 400, such as at leastabout 600, such as at least about 1000. The cell, may, for example, beselected from the group consisting of a human cell, a monkey cell and amouse cell. In some embodiments, the cell is a neuronal cell, such as ahuman neuronal cell, such as an iCell® GlutaNeuron cell (for moreinformation on these cells, see Table 2). Particularly suitable assaysare described in Examples 14 and 16.

Typically, an oligonucleotide according to the invention also oralternatively has a low toxicity. Suitably, this can be tested in an invitro assay, such as, e.g., in any one or more of the assays describedin Example 7.

An aspect of the present invention relates to an antisenseoligonucleotide, such as an LNA antisense oligonucleotide gapmer whichcomprises a contiguous nucleotide sequence of 10 to 30 nucleotides inlength with at least 90% complementarity, such as is fully complementaryto SEQ ID NO:1, 2 or 3.

In some embodiments, the oligonucleotide comprises a contiguous sequenceof 10-30 nucleotides, which is at least 90% complementary, such as atleast 91%, such as at least 92%, such as at least 93%, such as at least94%, such as at least 95%, such as at least 96%, such as at least 97%,such as at least 98%, or 100% complementary with a region of the targetnucleic acid or a target sequence. The sequences of suitable targetnucleic acids are described herein above.

In some embodiments, the oligonucleotide of the invention comprises acontiguous nucleotides sequence of 12-24, such as 13, 14, 15, 16, 17,18, 19, 20, 21, 22, or 23, contiguous nucleotides in length, wherein thecontiguous nucleotide sequence is fully complementary to a targetnucleic acid having a sequence as provided in the section “Tagetsequence regions” above.

In some embodiments, the antisense oligonucleotide of the inventioncomprises a contiguous nucleotides sequence of 12-15, such as 13, or 14,15 contiguous nucleotides in length, wherein the contiguous nucleotidesequence is fully complementary to a target nucleic acid having asequence as provided in the section “Target sequence regions” above.

Typically, the antisense oligonucleotide of the invention or thecontiguous nucleotide sequence thereof is a gapmer, such as an LNAgapmer, a mixed wing gapmer, or an alternating flank gapmer.

In some embodiments, the antisense oligonucleotide according to theinvention, comprises a contiguous nucleotide sequence of at least 10contiguous nucleotides, such as at least 12 contiguous nucleotides, suchas at least 13 contiguous nucleotides, such as at least 14 contiguousnucleotides, such as at least 15 contiguous nucleotides, which is fullycomplementary to a target sequence comprised in a sequence selected fromSEQ ID NO:1098, SEQ ID NO:1992, or both.

In some embodiments, the target sequence region of an antisenseoligonucleotide according to the invention comprises or consists of SEQID NO:1098.

In some embodiments, the target sequence region of an antisenseoligonucleotide according to the invention comprises or consists of SEQID NO:1992.

In some embodiments the contiguous nucleotide sequence of the antisenseoligonucleotide according to the invention is less than 20 nucleotidesin length. In some embodiments the contiguous nucleotide sequence of theantisense oligonucleotide according to the invention is 12-24nucleotides in length. In some embodiments the contiguous nucleotidesequence of the antisense oligonucleotide according to the invention is12-22 nucleotides in length. In some embodiments the contiguousnucleotide sequence of the antisense oligonucleotide according to theinvention is 12-20 nucleotides in length. In some embodiments thecontiguous nucleotide sequence of the antisense oligonucleotideaccording to the invention is 12-18 nucleotides in length. In someembodiments the contiguous nucleotide sequence of the antisenseoligonucleotide according to the invention is 12-16 nucleotides inlength.

Advantageously, in some embodiments all of the internucleoside linkagesbetween the nucleosides of the contiguous nucleotide sequence arephosphorothioate internucleoside linkages.

In some embodiments, the contiguous nucleotide sequence is fullycomplementary to a target nucleic acid.

The oligonucleotide compounds represent specific designs of a motifsequence. Typically, capital letters or the HELM-designation [LR]represent beta-D-oxy LNA nucleosides, lowercase letters or [dR]represent DNA nucleosides, all LNA C are 5-methyl cytosine, and 5-methylDNA cytosines are presented by “e” or mc or [5meC], and allinternucleoside linkages are, unless otherwise indicated,stereoundefined phosphorothioate internucleoside linkages [sP].

Design refers to the gapmer design, F-G-F′, where each number representsthe number of consecutive modified nucleosides, e.g. 2′ modifiednucleosides (first number=5′ flank), followed by the number of DNAnucleosides (second number=gap region), followed by the number ofmodified nucleosides, e.g. 2′ modified nucleosides (third number=3′flank), optionally preceded by or followed by further repeated regionsof DNA and LNA, which are not necessarily part of the contiguousnucleotide sequence that is complementary to the target nucleic acid.

Motif sequences represent the contiguous sequence of nucleobases presentin the oligonucleotide, also referred to as the Oligonucleotide BaseSequence.

Typically, the antisense oligonucleotides is 12-24, such as 12-18,nucleosides in length wherein the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising at least 12, such as at least14, such as at least 15 contiguous nucleotides present in a sequenceselected from SEQ ID NO:1122 and SEQ ID NO:1816, with one or more of thefurther modifications described herein.

In some embodiments, the antisense oligonucleotide is a gapmeroligonucleotide comprising a contiguous nucleotide sequence of formula5′-F-G-F′-3′, where region F and F′ independently comprise 1-8 sugarmodified nucleosides, and G is a region between 5 and 16 nucleosideswhich are capable of recruiting RNaseH.

In some embodiments, the sugar-modified nucleosides of region F and F′are independently selected from the group consisting of 2′-O-alkyl-RNA,2′-O-methyl-RNA, 2′-O-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA,2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNAnucleosides.

In some embodiments, region G comprises 5-16 contiguous DNA nucleosides.

In some embodiments, the antisense oligonucleotide is an LNA gapmeroligonucleotide comprising LNA nucleosides.

In some embodiments, the LNA nucleosides are beta-D-oxy LNA nucleosides.

In some embodiments, substantially all, or all of the internucleosidelinkages between the contiguous nucleosides are phosphorothioateinternucleoside linkages.

In some embodiments, substantially all, or all phosphorothioateinternucleoside linkages between the contiguous nucleosides arestereo-undefined phosphorothioate internucleoside linkages.

In some embodiments, one or more internucleoside linkages between thecontiguous nucleosides are stereodefined phosphorothioateinternucleoside linkages.

Particular sequence motifs and antisense oligonucleotides of the presentinvention are shown in Table 11 of Example 13, wherein each compoundrepresents a separate specific embodiment according to the invention.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising the base sequence of anantisense oligonucleotide selected from the group consisting of CompoundID Nos. 1122_82 to 1122_336, shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof an antisense oligonucleotide selected from the group consisting ofCompound ID Nos. 1122_82 to 1122_336, shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises acontiguous nucleotide sequence comprising the nucleoside base sequenceand, optionally, the sugar moiety modifications, of an antisenseoligonucleotide selected from the group consisting of Compound ID Nos.1122_91, 1122_107, 1122_154, 1122_155, 1122_156, 1122_157, 1122_158,1122_167, 1122_172, 1122_175, 1122_294, and 1122_296, shown in Table 14.

In one aspect, the antisense oligonucleotide is an LNA gapmer antisenseoligonucleotide comprising a contiguous nucleotide sequence comprisingthe contiguous nucleotides present in SEQ ID NO:1122 except for themodified nucleosides and modified intemucleoside linkages indicated inTable 15 for each residue in SEQ ID NO:1122. In a specific embodiment,the antisense oligonucleotide is more capable of inhibiting theexpression of human ATXN3 than human KCNB2 in a cell which is expressinghuman ATXN3 and human KCNB2.

In one embodiment, the LNA gapmer antisense oligonucleotide comprisesthe contiguous nucleotides present in SEQ ID NO:1122, wherein allinternucleoside linkages are stereo-undefined phosphorothioateinternucleoside linkages, wherein 2, 3 or 4 of the nucleosides in eachof region F and region F′ are beta-D-oxy LNA nucleosides [LR], typicallywherein each beta-D-oxy LNA cytosine is 5-methyl cytosine [LR](5meC),except for:

-   -   (a) residue 10 being a 2′-O-methyl uracil nucleoside [mR](U)        (e.g., Compound ID No. 1122_91);    -   (b) residue 3 being a 2′-O-methyl uracil nucleoside [mR](U)        (e.g., Compound ID No. 1122_107);    -   (c) the intemucleoside linkage between residues 11 and 12 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1122_154);    -   (d) the intemucleoside linkage between residues 12 and 13 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1122_155);    -   (e) the intemucleoside linkage between residues 13 and 14 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1122_156);    -   (f) the intemucleoside linkage between residues 14 and 15 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1122_157);    -   (g) the intemucleoside linkage between residues 15 and 16 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1122_158);    -   (h) residue 7 being a 2′-O-methoxyethyl adenine nucleoside        [MOE](A) (e.g., Compound ID No. 1122_167);    -   (i) residue 15 being a 2′-O-methyl cytosine nucleoside [mR](C)        (e.g., Compound ID NO. 1122_172);    -   (j) residue 11 being a 2′-O-methyl adenine nucleoside [mR](A)        (e.g., Compound ID No. 1122_175);    -   (k) residue 18 being a 2′-fluoro cytosine nucleoside [fR](C)        (e.g., Compound ID No. 1122_294);    -   (l) residue 4 being a 2′-O-methyl cytosine nucleoside [mR](C)        (e.g., Compound ID No. 1122_296); or    -   (m) a combination of any two or more of (a) to (l).

In some embodiments, the one or more modified nucleosides and/or one ormore modified intemucleoside linkages are, for each residue in SEQ IDNO:1122, independently selected from the options for that residue asshown in Table 15.

In one aspect, the antisense oligonucleotide is an LNA gapmer antisenseoligonucleotide comprising a contiguous nucleotide sequence comprisingthe contiguous nucleotides present in SEQ ID NO:1816 except for themodified nucleosides and modified internucleoside linkages indicated inTable 16 for each residue in SEQ ID NO:1816. In a specific embodiment,the antisense oligonucleotide is more capable of inhibiting theexpression of human ATXN3 than human KCNB2 in a cell which is expressinghuman ATXN3 and human KCNB2.

In one embodiment, the LNA gapmer antisense oligonucleotide comprisesthe contiguous nucleotides present in SEQ ID NO:1816, wherein allinternucleoside linkages are stereo-undefined phosphorothioateinternucleoside linkages, wherein 4, 5 or 6 of the nucleosides in theF-region and 2 or 3 of the nucleosides in the F′-region are beta-D-oxyLNA nucleosides [LR], typically wherein each beta-D-oxy LNA cytosine is5-methyl cytosine [LR](5meC), except for:

-   -   (a) the internucleoside linkage between residues 12 and 13 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1816_13);    -   (b) the internucleoside linkage between residues 14 and 15 being        a stereodefined phosphorothioate internucleoside linkage [ssP]        (e.g., Compound ID No. 1816_15);    -   (c) residue 8 being a 2′-fluoro adenine nucleoside [fR](A)        (e.g., Compound ID No. 1816_28);    -   (d) residues 1, 2, 3, 5, 7, 8, 16, 17 and 18 being LNA        beta-D-oxy LNA nucleosides [LR], wherein each beta-D-oxy LNA        cytosine is 5-methyl cytosine [LR](5meC) (e.g, Compound ID No.        1816_41);    -   (e) residue 17 being a 2′-O-methoxyethyl thymine nucleoside        [MOE](T) (e.g., Compound ID No. 1816_42);    -   (0 residue 16 being a 2′-O-methoxyethyl cytosine nucleoside        [MOE](5meC) (e.g., Compound ID No. 1816_43);    -   (g) residue 8 being a 2′-O-methyl adenine nucleoside [mR](A)        (e.g., Compound ID No. 1816_60);    -   (h) residue 3 being a 2′-O-methyl adenine nucleoside [mR](A)        (e.g., Compound ID No. 1816_61);    -   (i) residue 16 being a 2′-O-fluoro cytosine nucleoside [fR](C)        (e.g., Compound ID No. 1816_64);    -   (j) residue 16 being a 2′-O-methyl cytosine nucleoside [mR](C)        (e.g., Compound ID No. 1816_65);    -   (k) residue 17 being a 2′-fluoro uracil nucleoside [fR](U)        (e.g., Compound ID No. 1816_68); or    -   (l) a combination of any two or more of (a) to (k).

In some embodiments, the one or more modified nucleosides and/or one ormore modified internucleoside linkages are, for each residue in SEQ IDNO:1816, independently selected from the options for that residue asshown in Table 16.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_91, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_107, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_154, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_155, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_156, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_157, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_158, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_167, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_172, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_175, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_294, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1122_296, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_13, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_15, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_28, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_41, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_42, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_43, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_60, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_61, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_64, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_65, as shown in Table 11.

In some embodiments, the antisense oligonucleotide comprises or consistsof Compound ID No. 1816_68, as shown in Table 11.

In some embodiments, the antisense oligonucleotide is an antisenseoligonucleotide according to the following chemical annotation:

-   -   (a)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([m R])U_([sP]).^([dR])(A)_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C)_([sP]).^([LR][5me])C        (SEQ ID NO:1122, wherein residue 10 is U) (Compound ID No.        1122_91);    -   (b)        ^([LR])A_([sP]).^([LR])A_([sP]).^([mR])U_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([LR])T_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122, wherein residue 3 is U) (Compound ID No.        1122_107);    -   (c)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([ssP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_154);    -   (d)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_155);    -   (e)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([ssP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_156);    -   (f)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([ssP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_157);    -   (g)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([ssP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_158);    -   (h)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([MOE])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_167);    -   (i)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_172);    -   (j)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_175);    -   (k)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([fR])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_294);    -   (l)        ^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([s P]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C        (SEQ ID NO:1122) (Compound ID No. 1122_296);    -   (m)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([ssP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_13);    -   (n)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([ssP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_15);    -   (o)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([fR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_28);    -   (p)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_41);    -   (q)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([MOE])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_42);    -   (r)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([MOE][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_43);    -   (s)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([mR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_60);    -   (t)        ^([LR])G_([sP]).^([LR])A_([sP]).^([mR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_61);    -   (u)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([fR])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_64);    -   (v)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([LR])T_([sP]).^([LR])T        (SEQ ID NO:1816) (Compound ID No. 1816_65); or    -   (w)        ^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([fR])U_([sP]).^([LR])T        (SEQ ID NO:1816, wherein residue 17 is U)(Compound ID No.        1816_68),    -   or is a pharmaceutically acceptable salt thereof, wherein    -   [LR] is a beta-D-oxy-LNA nucleoside,    -   [LR][5me]C is a beta-D-oxy-LNA 5-methyl cytosine nucleoside,    -   [dR] is a DNA nucleoside,    -   [sP] is a phosphorothioate internucleoside linkage (stereo        undefined)    -   [ssP] is a stereodefined Sp phosphorothioate internucleoside        linkage    -   [mR] is a 2′-O-methyl nucleoside,    -   [MOE] is a 2′-O-methoxyethyl nucleoside, and    -   [fR] is a 2′-fluoro nucleoside.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12A (Compound ID No. 1122_91); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12B (Compound ID No. 1122_107); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12C (Compound ID No. 1122_154); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12D (Compound ID No. 1122_155); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12E (Compound ID No. 1122_156); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12F (Compound ID No. 1122_157); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12G (Compound ID No. 1122_158); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12H (Compound ID No. 1122_167); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12I (Compound ID No. 1122_172); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12J (Compound ID No. 1122_175); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12K (Compound ID No. 1122_294); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12L (Compound ID No. 1122_296); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12M (Compound ID No. 1816_13); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12N (Compound ID No. 1816_15); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12O (Compound ID No. 1816_28); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12P (Compound ID No. 1816_41); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12Q (Compound ID No. 1816_42); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12R (Compound ID No. 1816_43); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12S (Compound ID No. 1816_60); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12T (Compound ID No. 1816_61); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12U (Compound ID No. 1816_64); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12V (Compound ID No. 1816_65); or apharmaceutically acceptable salt thereof.

In one embodiment, the antisense oligonucleotide is the antisenseoligonucleotide shown in FIG. 12W (Compound ID No. 1816_68); or apharmaceutically acceptable salt thereof.

III. Compositions, Methods, and Applications for Inhibition of ATXN3Expression

A. Method of Manufacture

In a further aspect, the invention provides methods for manufacturingthe oligonucleotides of the invention comprising reacting nucleotideunits and thereby forming covalently linked contiguous nucleotide unitscomprised in the oligonucleotide. Preferably, the method usesphophoramidite chemistry (see for example Caruthers et al, 1987, Methodsin Enzymology vol. 154, pages 287-313). In a further embodiment themethod further comprises reacting the contiguous nucleotide sequencewith a conjugating moiety (ligand) to covalently attach the conjugatemoiety to the oligonucleotide. In a further aspect a method is providedfor manufacturing the composition of the invention, comprising mixingthe oligonucleotide or conjugated oligonucleotide of the invention witha pharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.

B. Pharmaceutical Composition

In a further aspect, the invention provides pharmaceutical compositionscomprising any of the aforementioned oligonucleotides and/oroligonucleotide conjugates or salts thereof and a pharmaceuticallyacceptable diluent, carrier, salt and/or adjuvant.

In a further aspect, the invention provides pharmaceutical compositionscomprising any of the aforementioned oligonucleotides and/oroligonucleotide conjugates or salts thereof and a pharmaceuticallyacceptable diluent, carrier, salt or adjuvant.

A pharmaceutically acceptable diluent includes phosphate-buffered saline(PBS) and pharmaceutically acceptable salts include, but are not limitedto, sodium and potassium salts. In some embodiments the pharmaceuticallyacceptable diluent is sterile phosphate buffered saline. In someembodiments the oligonucleotide is used in the pharmaceuticallyacceptable diluent at a concentration of 50-300 μM solution.

The compounds according to the present invention may exist in the formof their pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of the present invention and are formed fromsuitable non-toxic organic or inorganic acids or organic or inorganicbases. Acid-addition salts include for example those derived frominorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, andthose derived from organic acids such as p-toluenesulfonic acid,salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citricacid, malic acid, lactic acid, fumaric acid, and the like. Base-additionsalts include those derived from ammonium, potassium, sodium and,quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceuticalcompound into a salt is a technique well known to pharmaceuticalchemists in order to obtain improved physical and chemical stability,hygroscopicity, flowability and solubility of compounds. It is forexample described in Bastin, Organic Process Research & Development2000, 4, 427-435 or in Ansel, In: Pharmaceutical Dosage Forms and DrugDelivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. For example,the pharmaceutically acceptable salt of the compounds provided hereinmay be a sodium salt.

Suitable formulations for use in the present invention are found inRemington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa., 17th ed., 1985. For a brief review of methods fordrug delivery, see, e.g., Langer (Science 249:1527-1533, 1990). WO2007/031091 provides further suitable and preferred examples ofpharmaceutically acceptable diluents, carriers and adjuvants (herebyincorporated by reference). Suitable dosages, formulations,administration routes, compositions, dosage forms, combinations withother therapeutic agents, pro-drug formulations are also provided inWO2007/031091.

Oligonucleotides or oligonucleotide conjugates of the invention may bemixed with pharmaceutically acceptable active or inert substances forthe preparation of pharmaceutical compositions or formulations.Compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but notlimited to, route of administration, extent of disease, or dose to beadministered.

These compositions may be sterilized by conventional sterilizationtechniques, or may be sterile filtered. The resulting aqueous solutionsmay be packaged for use as is, or lyophilized, the lyophilizedpreparation being combined with a sterile aqueous carrier prior toadministration. The pH of the preparations typically will be between 3and 11, more preferably between 5 and 9 or between 6 and 8, and mostpreferably between 7 and 8, such as 7 to 7.5. The resulting compositionsin solid form may be packaged in multiple single dose units, eachcontaining a fixed amount of the above-mentioned agent or agents, suchas in a sealed package of tablets or capsules. The composition in solidform can also be packaged in a container for a flexible quantity, suchas in a squeezable tube designed for a topically applicable cream orointment.

In some embodiments, the oligonucleotide or oligonucleotide conjugate ofthe invention is a prodrug. In particular with respect tooligonucleotide conjugates the conjugate moiety is cleaved of theoligonucleotide once the prodrug is delivered to the site of action,e.g. the target cell.

C. Applications

The oligonucleotides of the invention may be utilized as researchreagents for, for example, diagnostics, therapeutics and prophylaxis.

In research, such oligonucleotides may be used to specifically modulatethe synthesis of ATXN3 protein in cells (e.g. in vitro cell cultures)and experimental animals thereby facilitating functional analysis of thetarget or an appraisal of its usefulness as a target for therapeuticintervention. Typically the target modulation is achieved by degradingor inhibiting the mRNA producing the protein, thereby prevent proteinformation or by degrading or inhibiting a modulator of the gene or mRNAproducing the protein.

If employing the oligonucleotide of the invention in research ordiagnostics the target nucleic acid may be a cDNA or a synthetic nucleicacid derived from DNA or RNA.

The present invention provides an in vivo or in vitro method formodulating ATXN3 expression in a target cell which is expressing ATXN3,said method comprising administering an oligonucleotide of the inventionin an effective amount to said cell.

In some embodiments, the target cell, is a mammalian cell in particulara human cell. The target cell may be an in vitro cell culture or an invivo cell forming part of a tissue in a mammal.

In diagnostics the oligonucleotides may be used to detect and quantitateATXN3 expression in cell and tissues by northern blotting, in-situhybridisation or similar techniques.

For therapeutics, an animal or a human, suspected of having a disease ordisorder, which can be treated by modulating the expression of ATXN3

The invention provides methods for treating or preventing a disease,comprising administering a therapeutically or prophylactically effectiveamount of an oligonucleotide, an oligonucleotide conjugate or apharmaceutical composition of the invention to a subject suffering fromor susceptible to the disease.

The invention also relates to an oligonucleotide, a composition or aconjugate as defined herein for use as a medicament.

The oligonucleotide, oligonucleotide conjugate or a pharmaceuticalcomposition according to the invention is typically administered in aneffective amount.

The invention also provides for the use of the oligonucleotide oroligonucleotide conjugate of the invention as described for themanufacture of a medicament for the treatment of a disorder as referredto herein, or for a method of the treatment of as a disorder as referredto herein.

The disease or disorder, as referred to herein, is associated withexpression of ATXN3. In some embodiments disease or disorder may beassociated with a mutation in the ATXN3 gene. Therefore, in someembodiments, the target nucleic acid is a mutated form of the ATXN3sequence.

The methods of the invention are preferably employed for treatment orprophylaxis against diseases caused by abnormal levels and/or activityof ATXN3.

The invention further relates to use of an oligonucleotide,oligonucleotide conjugate or a pharmaceutical composition as definedherein for the manufacture of a medicament for the treatment of abnormallevels and/or activity of ATXN3.

In one embodiment, the invention relates to oligonucleotides,oligonucleotide conjugates or pharmaceutical compositions for use in thetreatment of spinocerebellar ataxia.

D. Administration

In some embodiments, the oligonucleotides or pharmaceutical compositionsof the present invention may be administered oral. In furtherembodiments, the oligonucleotides or pharmaceutical compositions of thepresent invention may be administered topical or enteral or parenteral(such as, intravenous, subcutaneous, intra-muscular, intracerebral,intracerebroventricular or intrathecal).

In a preferred embodiment the oligonucleotide or pharmaceuticalcompositions of the present invention are administered by a parenteralroute including intravenous, intraarterial, subcutaneous,intraperitoneal or intramuscular injection or infusion, intrathecal orintracranial, e.g. intracerebral or intraventricular, intravitrealadministration. In one embodiment the active oligonucleotide oroligonucleotide conjugate is administered intravenously. In anotherembodiment the active oligonucleotide or oligonucleotide conjugate isadministered subcutaneously.

In some embodiments, the oligonucleotide, oligonucleotide conjugate orpharmaceutical composition of the invention is administered at a dose of0.1-15 mg/kg, such as from 0.2-10 mg/kg, such as from 0.25-5 mg/kg. Theadministration can be once a week, every 2^(nd) week, every third weekor even once a month.

E. Combination therapies

In some embodiments the oligonucleotide, oligonucleotide conjugate orpharmaceutical composition of the invention is for use in a combinationtreatment with another therapeutic agent. The therapeutic agent can forexample be the standard of care for the diseases or disorders describedabove.

EXAMPLES Materials and Methods:

Oligonucleotide Synthesis:

Oligonucleotide synthesis is generally known in the art. Below is aprotocol which may be applied. The oligonucleotides of the presentinvention may have been produced by slightly varying methods in terms ofapparatus, support and concentrations used.

Oligonucleotides are synthesized on uridine universal supports using thephosphoramidite approach on an MermMade 192 oligonucleotide synthesizerat 1 μmol scale. At the end of the synthesis, the oligonucleotides arecleaved from the solid support using aqueous ammonia for 5-16 hours at60° C. The oligonucleotides are purified by reverse phase HPLC (RP-HPLC)or by solid phase extractions and characterized by UPLC, and themolecular mass is further confirmed by ESI-MS.

Elongation of The Oligonucleotide:

The coupling of 5′DMTr protected nucleosideO-cyanoethyl-phosphoramidites, including DNA-A(Bz), DNA-G(iBu),DNA-C(Bz), DNA-T, LNA-5-methyl-C(Bz), LNA-A(Bz), LNA-G(dmf), LNA-T,MOE-A(Bz), MOE-G(iBu), MOE-(T), MOE-(U), MOE-5-methyl-C(Bz), 2′F-A(Bz),2′F(T), 2′F(U), 2′F—C(Ac), 2′F-G(iBu), 2′ OMe-A(Bz), 2′ OMe(U), 2′OMe(T), 2′ OMe-C(Ac), 2′ OMe-G(iBu), 2′OMe-G(dmf) is performed by usinga solution of 0.1 M of the 5′-O-DMT-protected amidite in acetonitrileand DCI (4,5-dicyanoimidazole) in acetonitrile (0.25 M) as activator.

Purification by RP-HPLC:

The crude compounds are purified by preparative RP-HPLC on a PhenomenexJupiter C18 10μ 150×10 mm column. 0.1 M ammonium acetate pH 8 andacetonitrile is used as buffers at a flow rate of 5 mL/min. Thecollected fractions are lyophilized to give the purified compoundtypically as a white solid.

Abbreviations:

-   -   DCI: 4,5-Dicyanoimidazole    -   DCM: Dichloromethane    -   DMF: Dimethylformamidine    -   DMT: 4,4′-Dimethoxytrityl    -   THF: Tetrahydrofurane    -   Bz: Benzoyl    -   Ibu: Isobutyryl    -   RP-HPLC: Reverse phase high performance liquid chromatography

T_(m) Assay:

Oligonucleotide and RNA target (phosphate linked, PO) duplexes arediluted to 3 mM in 500 ml RNase-free water and mixed with 500 ml2×T_(m)-buffer (200 mM NaCl, 0.2 mM EDTA, 20 mM Naphosphate, pH 7.0).The solution is heated to 95° C. for 3 min and then allowed to anneal inroom temperature for 30 min. The duplex melting temperatures (T_(m)) ismeasured on a Lambda 40 UV/VIS Spectrophotometer equipped with a Peltiertemperature programmer PTP6 using PE Templab software (Perkin Elmer).The temperature is ramped up from 20° C. to 95° C. and then down to 25°C., recording absorption at 260 nm. First derivative and the localmaximums of both the melting and annealing are used to assess the duplexT_(m).

Cell Lines:

TABLE 2 Details in relation to the cell lines for assaying thecompounds: Hours of Cells/well cell incubation Cell lines (96 well priorto Days of Name Vendor Cat. no. Cell medium plate) treatment treatmentA431 ECACC 85090402 EMEM (Cat. no. 8000 24 3 M2279), 10% FBS (Cat. no.F7524), 2 mM Glutamine (Cat. no. G8541), 0.1 mM NEAA (Cat. no. M7145),25 μg/ml Gentamicin (Cat. no. G1397) NCI-H23 ATCC CRL-5800 RPMI 164010000 24 3 (Cat. no. R2405), 10% FBS (Cat. no. F7524), 10 mM Hepes (Cat.no. H0887), 1 mM Sodium Pyruvate (Cat. no. S8636), 25 μg/ml Gentamicin(Cat. no. G1397) ARPE19 ATCC CRL-2302 DMEM/F-12 HAM 2000 0 4 (Cat. no.D8437), 10% FBS (Cat. no. F7524), 25 μg/ml Gentamicin (Cat. no. G1397)U251 ECACC  9063001 EMEM (Cat. no. 2000 0 4 M2279), 10% FBS (Cat. no.F7524), 2 mM Glutamine (Cat. no. G8541), 0.1 mM NEAA (Cat. no. M7145), 1mM Sodium Pyruvate (Cat. no. S8636), 25 μg/ml Gentamicin (Cat. no.G1397) U2-OS ATCC HTB-96 MCCoy 5A medium 7000 24 3 (Cat. no. M8403), 10%FBS (Cat. no. F7524), 1.5 mM Glutamine (Cat. no. G8541), 25 μg/mlGentamicin (Cat. no. G1397) SK-N-AS ATCC CRL-2137 Dulbecco's Modified9300 24 4 Eagle's Medium, supplemented with 0.1 mM Non-Essential AminoAcids (NEAA) and fetal bovine serum to a final concentration of 10%iCell ® Stemcell R1034 BrainPhys Neuronal 50.000-80.000 168 4GlutaNeurons Technologies Medium (Cat. no. 5790) supplemented withiCell ® GlutaNeurons Kit (Stemcell Technologies. no. R1034) according tovendor), N-2 (Thermo Fisher), 1 μg/ml Laminin 512 (BioLamina, no.LN521) * All medium and additives are purchased from Sigma Aldrichunless otherweise stated.

Example 1: Testing in vitro efficacy of LNA oligonucleotides in SK-N-AS,A431, NCI-H23 and ARPE19 cell lines at 25 and 5 μM Materials andMethods:

An oligonucleotide screen is performed in human cell lines using the LNAoligonucleotides in Table 3 (CMP ID NO: 4_1-1089_1, see column“oligonucleotide compounds”) targeting SEQ ID NO: 1. The human celllines SK-N-AS, A341, NCI-H23 and ARPE19 are purchased from the vendorslisted in Table 2, and are maintained as recommended by the supplier ina humidified incubator at 37° C. with 5% CO₂. For the screening assays,cells are seeded in 96 multi well plates in media recommended by thesupplier (see Table 2 in the Materials and Methods section). The numberof cells/well is optimized for each cell line (see Table 2 in theMaterials and Methods section).

Cells are incubated between 0 and 24 hours before addition of theoligonucleotide in a concentration of 5 or 25 μM (dissolved in PBS). 3-4days after addition of the oligonucleotide, the cells are harvested (Theincubation times for each cell line are indicated in Table 2 in theMaterials and Methods section).

RNA is extracted using the Qiagen RNeasy 96 kit (74182), according tothe manufacturer's instructions). cDNA synthesis and qPCR is performedusing qScript XLT one-step RT-qPCR ToughMix Low ROX, 95134-100 (QuantaBiosciences). Target transcript levels are quantified using FAM labeledTaqMan assays from Thermo Fisher Scientific in a multiplex reaction witha VIC labelled GUSB control. TaqMan primer assays for the targettranscript of interest ATXN3 (see below) and a house keeping gene GUSB(4326320E VIC-MGB probe).

ATXN3 primer assay (Assay ID: N/A Item Name Hs.PT.58.39355049):Forward primer: (SEQ ID NO: 1128) GTTTCTAAAGACATGGTCACAGC Reverse:(SEQ ID NO: 1129) CTATCAGGACAGAGTTCACATCC Probe: (SEQ ID NO: 1130)56-FAM/AAAGGCCAG/ZEN/CCACCAGTTCAGG/3IABkFQ/

Results:

The relative ATXN3 mRNA expression levels are determined as % of control(PBS-treated cells) i.e. the lower the value the larger the inhibition.

TABLE 3Sequence Motifs and Compounds of Exemplary Compounds of the InventionOligonucleotide SEQ ID NO motif sequence start end design CMP ID NOcompound    4 aagaaaccaaaccc   743   756 2-10-2 4_1 AAgaaaccaaacCC    5aaagaaaccaaacc   744   757 2-10-2 5_1 AAagaaaccaaaCC    6 aaaagaaaccaaac  745   758 2-10-2 6_1 AAaagaaaccaaAC    7 caaaagaaaccaaa   746   7592-10-2 7_1 CAaaagaaaccaAA    8 ccaaaagaaaccaa   747   760 2-10-2 8_1CCaaaagaaaccAA    9 tccactcctaatac   803   816 2-10-2 9_1 TCcactcctaatAC  10 gtccactcctaata   804   817 2-10-2 10_1 GTccactcctaaTA   11agtccactcctaat   805   818 2-10-2 11_1 AGtccactcctaAT   12cagtccactcctaa   806   819 2-10-2 12_1 CAgtccactcctAA   13ccagtccactccta   807   820 2-10-2 13_1 CCagtccactccTA   14actctttccaaaca  1012  1025 2-10-2 14_1 ACtctttccaaaCA   15aactctttccaaac  1013  1026 2-10-2 15_1 AActctttccaaAC   16caactctttccaaa  1014  1027 2-10-2 16_1 CAactctttccaAA   17gcaactctttccaa  1015  1028 2-10-2 17_1 GCaactctttccAA   18agcaactctttcca  1016  1029 2-10-2 18_1 AGcaactctttcCA   19cagcaactctttcc  1017  1030 2-10-2 19_1 CAgcaactctttCC   20ccagcaactctttc  1018  1031 2-10-2 20_1 CCagcaactcttTC   21accagcaactcttt  1019  1032 2-10-2 21_1 ACcagcaactctTT   22ctcctattaaataa  1040  1053 2-10-2 22_1 CTcctattaaatAA   23cctcctattaaata  1041  1054 2-10-2 23_1 CCtcctattaaaTA   24tcctcctattaaat  1042  1055 2-10-2 24_1 TCctcctattaaAT   25ctcctcctattaaa  1043  1056 2-10-2 25_1 CTcctcctattaAA   26gctcctcctattaa  1044  1057 2-10-2 26_1 GCtcctcctattAA   27tgctcctcctatta  1045  1058 2-10-2 27_1 TGctcctcctatTA   28ttgctcctcctatt  1046  1059 2-10-2 28_1 TTgctcctcctaTT   29tttgctcctcctat  1047  1060 2-10-2 29_1 TTtgctcctcctAT   30ctttgctcctccta  1048  1061 2-10-2 30_1 CTttgctcctccTA   31cctttgctcctcct  1049  1062 2-10-2 31_1 CctttgctcctcCT   32ccctttgctcctcc  1050  1063 2-10-2 32_1 CCctttgctcctCC   33accctttgctcctc  1051  1064 2-10-2 33_1 ACcctttgctccTC   34aaccctttgctcct  1052  1065 2-10-2 34_1 AAccctttgctcCT   35aaaccctttgctcc  1053  1066 2-10-2 35_1 AAaccctttgctCC   36aaaaccctttgctc  1054  1067 2-10-2 36_1 AAaaccctttgcTC   37aaaaaccctttgct  1055  1068 2-10-2 37_1 AAaaaccctttgCT   38caaaaaccctttgc  1056  1069 2-10-2 38_1 CAaaaaccctttGC   39acaaaaaccctttg  1057  1070 2-10-2 39_1 ACaaaaacccttTG   40aacaaaaacccttt  1058  1071 2-10-2 40_1 AAcaaaaaccctTT   41aaacaaaaaccctt  1059  1072 2-10-2 41_1 AAacaaaaacccTT   42aaaacaaaaaccct  1060  1073 2-10-2 42_1 AAaacaaaaaccCT   43taaaacaaaaaccc  1061  1074 2-10-2 43_1 TAaaacaaaaacCC   44ataaaacaaaaacc  1062  1075 2-10-2 44_1 ATaaaacaaaaaCC   45aataaaacaaaaac  1063  1076 2-10-2 45_1 AAtaaaacaaaaAC   46taataaaacaaaaa  1064  1077 2-10-2 46_1 TAataaaacaaaAA   47ttaataaaacaaaa  1065  1078 2-10-2 47_1 TTaataaaacaaAA   48tttaataaaacaaa  1066  1079 2-10-2 48_1 TTtaataaaacaAA   49atttaataaaacaa  1067  1080 2-10-2 49_1 ATttaataaaacAA   50ttaaaataaaaatt  1194  1207 2-10-2 50_1 TTaaaataaaaaTT   51tttaaaataaaaat  1195  1208 2-10-2 51_1 TTtaaaataaaaAT   52ctttaaaataaaaa  1196  1209 2-10-2 52_1 CTttaaaataaaAA   53tctttaaaataaaa  1197  1210 2-10-2 53_1 TCtttaaaataaAA   54atctttaaaataaa  1198  1211 2-10-2 54_1 ATctttaaaataAA   55catctttaaaataa  1199  1212 2-10-2 55_1 CAtctttaaaatAA   56ccatctttaaaata  1200  1213 2-10-2 56_1 CCatctttaaaaTA   57tctaacttaataaa  2886  2899 2-10-2 57_1 TCtaacttaataAA   58ttctaacttaataa  2887  2900 2-10-2 58_1 TTctaacttaatAA   59attctaacttaata  2888  2901 2-10-2 59_1 ATtctaacttaaTA   60cattctaacttaat  2889  2902 2-10-2 60_1 CAttctaacttaAT   61acattctaacttaa  2890  2903 2-10-2 61_1 ACattctaacttAA   62tacattctaactta  2891  2904 2-10-2 62_1 TAcattctaactTA   63ttacattctaactt  2892  2905 2-10-2 63_1 TTacattctaacTT   64tttacattctaact  2893  2906 2-10-2 64_1 TTtacattctaaCT   65ttttacattctaac  2894  2907 2-10-2 65_1 TTttacattctaAC   66tttttacattctaa  2895  2908 2-10-2 66_1 TTtttacattctAA   67gtttttacattcta  2896  2909 2-10-2 67_1 GTttttacattcTA   68tgtttttacattct  2897  2910 2-10-2 68_1 TGtttttacattCT   69ctgtttttacattc  2898  2911 2-10-2 69_1 CTgtttttacatTC   70ttcaaatatttatt  2969  2982 2-10-2 70_1 TTcaaatatttaTT   71attcaaatatttat  2970  2983 2-10-2 71_1 ATtcaaatatttAT   72cattcaaatattta  2971  2984 2-10-2 72_1 CAttcaaatattTA   73ccattcaaatattt  2972  2985 2-10-2 73_1 CCattcaaatatTT   74cccattcaaatatt  2973  2986 2-10-2 74_1 CCcattcaaataTT   75ccccattcaaatat  2974  2987 2-10-2 75_1 CCccattcaaatAT   76gccccattcaaata  2975  2988 2-10-2 76_1 GCcccattcaaaTA   77tatacatttttttc  3173  3186 2-10-2 77_1 TAtacattttttTC   78atatacattttttt  3174  3187 2-10-2 78_1 ATatacatttttTT   79tatatacatttttt  3175  3188 2-10-2 79_1 TAtatacattttTT   80atatatacattttt  3176  3189 2-10-2 80_1 ATatatacatttTT   81aatatatacatttt  3177  3190 2-10-2 81_1 AAtatatacattTT   82aaatatatacattt  3178  3191 2-10-2 82_1 AAatatatacatTT   83caaatatatacatt  3179  3192 2-10-2 83_1 CAaatatatacaTT   84tcaaatatatacat  3180  3193 2-10-2 84_1 TCaaatatatacAT   85ttcaaatatataca  3181  3194 2-10-2 85_1 TTcaaatatataCA   86attcaaatatatac  3182  3195 2-10-2 86_1 ATtcaaatatatAC   87cattcaaatatata  3183  3196 2-10-2 87_1 CAttcaaatataTA   88ccattcaaatatat  3184  3197 2-10-2 88_1 CCattcaaatatAT   89tccattcaaatata  3185  3198 2-10-2 89_1 TCcattcaaataTA   90atccattcaaatat  3186  3199 2-10-2 90_1 ATccattcaaatAT   91tatccattcaaata  3187  3200 2-10-2 91_1 TAtccattcaaaTA   92ttatccattcaaat  3188  3201 2-10-2 92_1 TTatccattcaaAT   93tttatccattcaaa  3189  3202 2-10-2 93_1 TTtatccattcaAA   94ctttatccattcaa  3190  3203 2-10-2 94_1 CTttatccattcAA   95tctttatccattca  3191  3204 2-10-2 95_1 TCtttatccattCA   96ctctttatccattc  3192  3205 2-10-2 96_1 CTctttatccatTC   97tctctttatccatt  3193  3206 2-10-2 97_1 TCtctttatccaTT   98ccatatatatctca  3221  3234 2-10-2 98_1 CCatatatatctCA   99accatatatatctc  3222  3235 2-10-2 99_1 ACcatatatatcTC  100caccatatatatct  3223  3236 2-10-2 100_1 CAccatatatatCT  101gcaccatatatatc  3224  3237 2-10-2 101_1 GCaccatatataTC  102agcaccatatatat  3225  3238 2-10-2 102_1 AGcaccatatatAT  103cagcaccatatata  3226  3239 2-10-2 103_1 CAgcaccatataTA  104acagcaccatatat  3227  3240 2-10-2 104_1 ACagcaccatatAT  105aacagcaccatata  3228  3241 2-10-2 105_1 AAcagcaccataTA  106aaaacaaacaacaa  3462  3475 2-10-2 106_1 AAaacaaacaacAA  107taaaacaaacaaca  3463  3476 2-10-2 107_1 TAaaacaaacaaCA  108ctaaaacaaacaac  3464  3477 2-10-2 108_1 CTaaaacaaacaAC  109actaaaacaaacaa  3465  3478 2-10-2 109_1 ACtaaaacaaacAA  110aactaaaacaaaca  3466  3479 2-10-2 110_1 AActaaaacaaaCA  111gaactaaaacaaac  3467  3480 2-10-2 111_1 GAactaaaacaaAC  112agaactaaaacaaa  3468  3481 2-10-2 112_1 AGaactaaaacaAA  113cagaactaaaacaa  3469  3482 2-10-2 113_1 CAgaactaaaacAA  114ccagaactaaaaca  3470  3483 2-10-2 114_1 CCagaactaaaaCA  115accagaactaaaac  3471  3484 2-10-2 115_1 ACcagaactaaaAC  116atgttattatcccc  3882  3895 2-10-2 116_1 ATgttattatccCC  117tatgttattatccc  3883  3896 2-10-2 117_1 TAtgttattatcCC  118ctatgttattatcc  3884  3897 2-10-2 118_1 CTatgttattatCC  119tctatgttattatc  3885  3898 2-10-2 119_1 TCtatgttattaTC  120tacactctaactct  3908  3921 2-10-2 120_1 TAcactctaactCT  121ctacactctaactc  3909  3922 2-10-2 121_1 CTacactctaacTC  122tctacactctaact  3910  3923 2-10-2 122_1 TCtacactctaaCT  123ctctacactctaac  3911  3924 2-10-2 123_1 CTctacactctaAC  124tctctacactctaa  3912  3925 2-10-2 124_1 TCtctacactctAA  125ttctctacactcta  3913  3926 2-10-2 125_1 TTctctacactcTA  126cttctctacactct  3914  3927 2-10-2 126_1 CTtctctacactCT  127ccttctctacactc  3915  3928 2-10-2 127_1 CCttctctacacTC  128tacaacacaaatca  4102  4115 2-10-2 128_1 TAcaacacaaatCA  129ctacaacacaaatc  4103  4116 2-10-2 129_1 CTacaacacaaaTC  130actacaacacaaat  4104  4117 2-10-2 130_1 ACtacaacacaaAT  131aactacaacacaaa  4105  4118 2-10-2 131_1 AActacaacacaAA  132taactacaacacaa  4106  4119 2-10-2 132_1 TAactacaacacAA  133ctaactacaacaca  4107  4120 2-10-2 133_1 CTaactacaacaCA  134actaactacaacac  4108  4121 2-10-2 134_1 ACtaactacaacAC  135tactaactacaaca  4109  4122 2-10-2 135_1 TActaactacaaCA  136ctactaactacaac  4110  4123 2-10-2 136_1 CTactaactacaAC  137actactaactacaa  4111  4124 2-10-2 137_1 ACtactaactacAA  138cactactaactaca  4112  4125 2-10-2 138_1 CActactaactaCA  139acactactaactac  4113  4126 2-10-2 139_1 ACactactaactAC  140gacactactaacta  4114  4127 2-10-2 140_1 GAcactactaacTA  141agacactactaact  4115  4128 2-10-2 141_1 AGacactactaaCT  142tttacccccaacct  4173  4186 2-10-2 142_1 TTtacccccaacCT  143atttacccccaacc  4174  4187 2-10-2 143_1 ATttacccccaaCC  144catttacccccaac  4175  4188 2-10-2 144_1 CAtttacccccaAC  145tcatttacccccaa  4176  4189 2-10-2 145 1 TCatttacccccAA  146atcatttaccccca  4177  4190 2-10-2 146_1 ATcatttaccccCA  147aatcatttaccccc  4178  4191 2-10-2 147_1 AAtcatttacccCC  148aaatcatttacccc  4179  4192 2-10-2 148_1 AAatcatttaccCC  149caaatcatttaccc  4180  4193 2-10-2 149_1 CAaatcatttacCC  150ccaaatcatttacc  4181  4194 2-10-2 150 1 CCaaatcatttaCC  151accaaatcatttac  4182  4195 2-10-2 151_1 ACcaaatcatttAC  152taccaaatcattta  4183  4196 2-10-2 152_1 TAccaaatcattTA  153ctaccaaatcattt  4184  4197 2-10-2 153_1 CTaccaaatcatTT  154gctaccaaatcatt  4185  4198 2-10-2 154_1 GCtaccaaatcaTT  155tgctaccaaatcat  4186  4199 2-10-2 155_1 TGctaccaaatcAT  156ctgctaccaaatca  4187  4200 2-10-2 156_1 CTgctaccaaatCA  157actgctaccaaatc  4188  4201 2-10-2 157_1 ACtgctaccaaaTC  158aactgctaccaaat  4189  4202 2-10-2 158_1 AActgctaccaaAT  159aagctttaatcaaa  5102  5115 2-10-2 159_1 AAgctttaatcaAA  160caagctttaatcaa  5103  5116 2-10-2 160_1 CAagctttaatcAA  161tcaagctttaatca  5104  5117 2-10-2 161_1 TCaagctttaatCA  162atcaagctttaatc  5105  5118 2-10-2 162_1 ATcaagctttaaTC  163catcaagctttaat  5106  5119 2-10-2 163_1 CAtcaagctttaAT  164tcaaactatcccca  5131  5144 2-10-2 164_1 TCaaactatcccCA  165ctcaaactatcccc  5132  5145 2-10-2 165_1 CTcaaactatccCC  166tctcaaactatccc  5133  5146 2-10-2 166_1 TCtcaaactatcCC  167atctcaaactatcc  5134  5147 2-10-2 167_1 ATctcaaactatCC  168tatctcaaactatc  5135  5148 2-10-2 168_1 TAtctcaaactaTC  169ttatctcaaactat  5136  5149 2-10-2 169_1 TTatctcaaactAT  170cttatctcaaacta  5137  5150 2-10-2 170_1 CTtatctcaaacTA  171ccttatctcaaact  5138  5151 2-10-2 171_1 CCttatctcaaaCT  172cccttatctcaaac  5139  5152 2-10-2 172_1 CCcttatctcaaAC  173gcccttatctcaaa  5140  5153 2-10-2 173_1 GCccttatctcaAA  174tgcccttatctcaa  5141  5154 2-10-2 174_1 TGcccttatctcAA  175caaacttcatcaaa  5540  5553 2-10-2 175 1 CAaacttcatcaAA  176tcaaacttcatcaa  5541  5554 2-10-2 176_1 TCaaacttcatcAA  177atcaaacttcatca  5542  5555 2-10-2 177_1 ATcaaacttcatCA  178aatcaaacttcatc  5543  5556 2-10-2 178_1 AAtcaaacttcaTC  179aaatcaaacttcat  5544  5557 2-10-2 179_1 AAatcaaacttcAT  180gaaatcaaacttca  5545  5558 2-10-2 180_1 GAaatcaaacttCA  181tgaaatcaaacttc  5546  5559 2-10-2 181_1 TGaaatcaaactTC  182ttgaaatcaaactt  5547  5560 2-10-2 182_1 TTgaaatcaaacTT  183aacacaaatttcct  5693  5706 2-10-2 183_1 AAcacaaatttcCT  184taacacaaatttcc  5694  5707 2-10-2 184_1 TAacacaaatttCC  185ctaacacaaatttc  5695  5708 2-10-2 185_1 CTaacacaaattTC  186gctaacacaaattt  5696  5709 2-10-2 186_1 GCtaacacaaatTT  187tgctaacacaaatt  5697  5710 2-10-2 187_1 TGctaacacaaaTT  188ttgctaacacaaat  5698  5711 2-10-2 188_1 TTgctaacacaaAT  189tttgctaacacaaa  5699  5712 2-10-2 189_1 TTtgctaacacaAA  190ctttgctaacacaa  5700  5713 2-10-2 190_1 CTttgctaacacAA  191cctttgctaacaca  5701  5714 2-10-2 191_1 CctttgctaacaCA  192taactaataattat  6417  6430 2-10-2 192_1 TAactaataattAT  193ataactaataatta  6418  6431 2-10-2 193_1 ATaactaataatTA  194aataactaataatt  6419  6432 2-10-2 194_1 AAtaactaataaTT  195taataactaataat  6420  6433 2-10-2 195_1 TAataactaataAT  196ataataactaataa  6421  6434 2-10-2 196_1 ATaataactaatAA  197aataataactaata  6422  6435 2-10-2 197_1 AAtaataactaaTA  198caataataactaat  6423  6436 2-10-2 198_1 CAataataactaAT  199ccaataataactaa  6424  6437 2-10-2 199_1 CCaataataactAA  200accaataataacta  6425  6438 2-10-2 200_1 ACcaataataacTA  201aaccaataataact  6426  6439 2-10-2 201_1 AAccaataataaCT  202taaccaataataac  6427  6440 2-10-2 202_1 TAaccaataataAC  203ataaccaataataa  6428  6441 2-10-2 203_1 ATaaccaataatAA  204tataaccaataata  6429  6442 2-10-2 204_1 TAtaaccaataaTA  205gtataaccaataat  6430  6443 2-10-2 205_1 GTataaccaataAT  206acatcacacaattt  7415  7428 2-10-2 206_1 ACatcacacaatTT  207gacatcacacaatt  7416  7429 2-10-2 207_1 GAcatcacacaaTT  208tgacatcacacaat  7417  7430 2-10-2 208_1 TGacatcacacaAT  209ctgacatcacacaa  7418  7431 2-10-2 209_1 CTgacatcacacAA  210tctgacatcacaca  7419  7432 2-10-2 210_1 TCtgacatcacaCA  211atctgacatcacac  7420  7433 2-10-2 211 1 ATctgacatcacAC  212ttccttaacccaac  7436  7449 2-10-2 212_1 TTccttaacccaAC  213attccttaacccaa  7437  7450 2-10-2 213_1 ATtccttaacccAA  214tattccttaaccca  7438  7451 2-10-2 214_1 TAttccttaaccCA  215ctattccttaaccc  7439  7452 2-10-2 215_1 CTattccttaacCC  216tctattccttaacc  7440  7453 2-10-2 216_1 TCtattccttaaCC  217gtctattccttaac  7441  7454 2-10-2 217_1 GTctattccttaAC  218catcaaatctcata  8609  8622 2-10-2 218_1 CAtcaaatctcaTA  219gcatcaaatctcat  8610  8623 2-10-2 219_1 GCatcaaatctcAT  220tgcatcaaatctca  8611  8624 2-10-2 220_1 TGcatcaaatctCA  221atgcatcaaatctc  8612  8625 2-10-2 221_1 ATgcatcaaatcTC  222aatgcatcaaatct  8613  8626 2-10-2 222_1 AAtgcatcaaatCT  223attttaaacaaaca  8637  8650 2-10-2 223_1 ATtttaaacaaaCA  224tattttaaacaaac  8638  8651 2-10-2 224_1 TAttttaaacaaAC  225ttattttaaacaaa  8639  8652 2-10-2 225_1 TTattttaaacaAA  226attattttaaacaa  8640  8653 2-10-2 226_1 ATtattttaaacAA  227aattattttaaaca  8641  8654 2-10-2 227_1 AAttattttaaaCA  228gaattattttaaac  8642  8655 2-10-2 228_1 GAattattttaaAC  229ttttacaaatctac  8693  8706 2-10-2 229_1 TTttacaaatctAC  230attttacaaatcta  8694  8707 2-10-2 230_1 ATtttacaaatcTA  231tattttacaaatct  8695  8708 2-10-2 231_1 TAttttacaaatCT  232ttattttacaaatc  8696  8709 2-10-2 232_1 TTattttacaaaTC  233tttattttacaaat  8697  8710 2-10-2 233_1 TTtattttacaaAT  234atttattttacaaa  8698  8711 2-10-2 234_1 ATttattttacaAA  235catttattttacaa  8699  8712 2-10-2 235_1 CAtttattttacAA  236acatttattttaca  8700  8713 2-10-2 236_1 ACatttattttaCA  237aacatttattttac  8701  8714 2-10-2 237_1 AAcatttattttAC  238taacatttatttta  8702  8715 2-10-2 238_1 TAacatttatttTA  239aatttaatcattaa  9391  9404 2-10-2 239_1 AAtttaatcattAA  240taatttaatcatta  9392  9405 2-10-2 240_1 TAatttaatcatTA  241ataatttaatcatt  9393  9406 2-10-2 241_1 ATaatttaatcaTT  242aataatttaatcat  9394  9407 2-10-2 242_1 AAtaatttaatcAT  243aaataatttaatca  9395  9408 2-10-2 243_1 AAataatttaatCA  244taaataatttaatc  9396  9409 2-10-2 244_1 TAaataatttaaTC  245ctaaataatttaat  9397  9410 2-10-2 245_1 CTaaataatttaAT  246cctaaataatttaa  9398  9411 2-10-2 246_1 CCtaaataatttAA  247ccctaaataattta  9399  9412 2-10-2 247_1 CCctaaataattTA  248cccctaaataattt  9400  9413 2-10-2 248_1 CCcctaaataatTT  249tcccctaaataatt  9401  9414 2-10-2 249_1 TCccctaaataaTT  250tatataaaaatcta 10958 10971 2-10-2 250_1 TAtataaaaatcTA  251ctatataaaaatct 10959 10972 2-10-2 251_1 CTatataaaaatCT  252tctatataaaaatc 10960 10973 2-10-2 252_1 TCtatataaaaaTC  253atctatataaaaat 10961 10974 2-10-2 253_1 ATctatataaaaAT  254tatctatataaaaa 10962 10975 2-10-2 254_1 TAtctatataaaAA  255ttatctatataaaa 10963 10976 2-10-2 255_1 TTatctatataaAA  256tttatctatataaa 10964 10977 2-10-2 256_1 TTtatctatataAA  257ccccactctaatat 11001 11014 2-10-2 257_1 CCccactctaatAT  258gccccactctaata 11002 11015 2-10-2 258_1 GCcccactctaaTA  259tgccccactctaat 11003 11016 2-10-2 259_1 TGccccactctaAT  260atgccccactctaa 11004 11017 2-10-2 260_1 ATgccccactctAA  261aatgccccactcta 11005 11018 2-10-2 261_1 AAtgccccactcTA  262aaatgccccactct 11006 11019 2-10-2 262_1 AAatgccccactCT  263taaatgccccactc 11007 11020 2-10-2 263_1 TAaatgccccacTC  264ttaaatgccccact 11008 11021 2-10-2 264_1 TTaaatgccccaCT  265atataaccaccaaa 11546 11559 2-10-2 265_1 ATataaccaccaAA  266tatataaccaccaa 11547 11560 2-10-2 266_1 TAtataaccaccAA  267atatataaccacca 11548 11561 2-10-2 267_1 ATatataaccacCA  268tatatataaccacc 11549 11562 2-10-2 268_1 TAtatataaccaCC  269atatatataaccac 11550 11563 2-10-2 269_1 ATatatataaccAC  270aaaattcactatct 11942 11955 2-10-2 270_1 AAaattcactatCT  271gaaaattcactatc 11943 11956 2-10-2 271_1 GAaaattcactaTC  272tgaaaattcactat 11944 11957 2-10-2 272_1 TGaaaattcactAT  273ctgaaaattcacta 11945 11958 2-10-2 273_1 CTgaaaattcacTA  274tctgaaaattcact 11946 11959 2-10-2 274_1 TCtgaaaattcaCT  275tactatatacatct 12176 12189 2-10-2 275_1 TActatatacatCT  276ctactatatacatc 12177 12190 2-10-2 276_1 CTactatatacaTC  277tctactatatacat 12178 12191 2-10-2 277_1 TCtactatatacAT  278gtctactatataca 12179 12192 2-10-2 278_1 GTctactatataCA  279agtctactatatac 12180 12193 2-10-2 279_1 AGtctactatatAC  280tagtctactatata 12181 12194 2-10-2 280_1 TAgtctactataTA  281ctagtctactatat 12182 12195 2-10-2 281_1 CTagtctactatAT  282actagtctactata 12183 12196 2-10-2 282_1 ACtagtctactaTA  283aactagtctactat 12184 12197 2-10-2 283_1 AActagtctactAT  284tattctacccataa 12211 12224 2-10-2 284_1 TAttctacccatAA  285atattctacccata 12212 12225 2-10-2 285_1 ATattctacccaTA  286tatattctacccat 12213 12226 2-10-2 286_1 TAtattctacccAT  287gtatattctaccca 12214 12227 2-10-2 287_1 GTatattctaccCA  288tgtatattctaccc 12215 12228 2-10-2 288_1 TGtatattctacCC  289atgtatattctacc 12216 12229 2-10-2 289_1 ATgtatattctaCC  290ccacacaattccta 12254 12267 2-10-2 290_1 CCacacaattccTA  291accacacaattcct 12255 12268 2-10-2 291_1 ACcacacaattcCT  292aaccacacaattcc 12256 12269 2-10-2 292_1 AAccacacaattCC  293aaaccacacaattc 12257 12270 2-10-2 293_1 AAaccacacaatTC  294aaaaccacacaatt 12258 12271 2-10-2 294_1 AAaaccacacaaTT  295gaaaaccacacaat 12259 12272 2-10-2 295_1 GAaaaccacacaAT  296agaaaaccacacaa 12260 12273 2-10-2 296_1 AGaaaaccacacAA  297cagaaaaccacaca 12261 12274 2-10-2 297_1 CAgaaaaccacaCA  298ccagaaaaccacac 12262 12275 2-10-2 298_1 CCagaaaaccacAC  299tccagaaaaccaca 12263 12276 2-10-2 299_1 TCcagaaaaccaCA  300aaatccataaaaaa 12327 12340 2-10-2 300_1 AAatccataaaaAA  301taaatccataaaaa 12328 12341 2-10-2 301 1 TAaatccataaaAA  302ctaaatccataaaa 12329 12342 2-10-2 302_1 CTaaatccataaAA  303actaaatccataaa 12330 12343 2-10-2 303_1 ACtaaatccataAA  304cactaaatccataa 12331 12344 2-10-2 304_1 CActaaatccatAA  305tcactaaatccata 12332 12345 2-10-2 305_1 TCactaaatccaTA  306atcactaaatccat 12333 12346 2-10-2 306_1 ATcactaaatccAT  307tatcactaaatcca 12334 12347 2-10-2 307_1 TAtcactaaatcCA  308atatcactaaatcc 12335 12348 2-10-2 308_1 ATatcactaaatCC  309tatatcactaaatc 12336 12349 2-10-2 309_1 TAtatcactaaaTC  310atatatcactaaat 12337 12350 2-10-2 310_1 ATatatcactaaAT  311gatatatcactaaa 12338 12351 2-10-2 311_1 GAtatatcactaAA  312agatatatcactaa 12339 12352 2-10-2 312_1 AGatatatcactAA  313tagatatatcacta 12340 12353 2-10-2 313_1 TAgatatatcacTA  314tataaatttctcta 12690 12703 2-10-2 314_1 TAtaaatttctcTA  315atataaatttctct 12691 12704 2-10-2 315_1 ATataaatttctCT  316tatataaatttctc 12692 12705 2-10-2 316_1 TAtataaatttcTC  317atatataaatttct 12693 12706 2-10-2 317_1 ATatataaatttCT  318catatataaatttc 12694 12707 2-10-2 318_1 CAtatataaattTC  319tcatatataaattt 12695 12708 2-10-2 319_1 TCatatataaatTT  320ctccattccaaatt 12739 12752 2-10-2 320_1 CTccattccaaaTT  321actccattccaaat 12740 12753 2-10-2 321_1 ACtccattccaaAT  322cactccattccaaa 12741 12754 2-10-2 322_1 CActccattccaAA  323ccactccattccaa 12742 12755 2-10-2 323_1 CCactccattccAA  324accactccattcca 12743 12756 2-10-2 324_1 ACcactccattcCA  325aaccactccattcc 12744 12757 2-10-2 325_1 AAccactccattCC  326aaaccactccattc 12745 12758 2-10-2 326_1 AAaccactccatTC  327tcacacaaccatat 13155 13168 2-10-2 327_1 TCacacaaccatAT  328atcacacaaccata 13156 13169 2-10-2 328_1 ATcacacaaccaTA  329gatcacacaaccat 13157 13170 2-10-2 329_1 GAtcacacaaccAT  330agatcacacaacca 13158 13171 2-10-2 330_1 AGatcacacaacCA  331aagatcacacaacc 13159 13172 2-10-2 331_1 AAgatcacacaaCC  332aaagatcacacaac 13160 13173 2-10-2 332_1 AAagatcacacaAC  333aaaagatcacacaa 13161 13174 2-10-2 333_1 AAaagatcacacAA  334taaaagatcacaca 13162 13175 2-10-2 334_1 TAaaagatcacaCA  335ttcatttctaaaaa 13297 13310 2-10-2 335_1 TTcatttctaaaAA  336tttcatttctaaaa 13298 13311 2-10-2 336_1 TTtcatttctaaAA  337ctttcatttctaaa 13299 13312 2-10-2 337_1 CTttcatttctaAA  338tctttcatttctaa 13300 13313 2-10-2 338_1 TCtttcatttctAA  339atctttcatttcta 13301 13314 2-10-2 339_1 ATctttcatttcTA  340gatctttcatttct 13302 13315 2-10-2 340_1 GAtctttcatttCT  341tgatctttcatttc 13303 13316 2-10-2 341_1 TGatctttcattTC  342atgatctttcattt 13304 13317 2-10-2 342_1 ATgatctttcatTT  343ataaaaacccactt 13990 14003 2-10-2 343_1 ATaaaaacccacTT  344cataaaaacccact 13991 14004 2-10-2 344_1 CAtaaaaacccaCT  345acataaaaacccac 13992 14005 2-10-2 345_1 ACataaaaacccAC  346cacataaaaaccca 13993 14006 2-10-2 346_1 CAcataaaaaccCA  347tcacataaaaaccc 13994 14007 2-10-2 347_1 TCacataaaaacCC  348atcacataaaaacc 13995 14008 2-10-2 348_1 ATcacataaaaaCC  349catcacataaaaac 13996 14009 2-10-2 349_1 CAtcacataaaaAC  350tcatcacataaaaa 13997 14010 2-10-2 350_1 TCatcacataaaAA  351gtcatcacataaaa 13998 14011 2-10-2 351_1 GTcatcacataaAA  352agtcatcacataaa 13999 14012 2-10-2 352_1 AGtcatcacataAA  353tagtcatcacataa 14000 14013 2-10-2 353_1 TAgtcatcacatAA  354atagtcatcacata 14001 14014 2-10-2 354_1 ATagtcatcacaTA  355catagtcatcacat 14002 14015 2-10-2 355_1 CAtagtcatcacAT  356taaatacaaatcta 14041 14054 2-10-2 356_1 TAaatacaaatcTA  357ctaaatacaaatct 14042 14055 2-10-2 357_1 CTaaatacaaatCT  358gctaaatacaaatc 14043 14056 2-10-2 358_1 GCtaaatacaaaTC  359tgctaaatacaaat 14044 14057 2-10-2 359_1 TGctaaatacaaAT  360atgctaaatacaaa 14045 14058 2-10-2 360_1 ATgctaaatacaAA  361tatgctaaatacaa 14046 14059 2-10-2 361_1 TAtgctaaatacAA  362aatcttacactaaa 14119 14132 2-10-2 362_1 AAtcttacactaAA  363taatcttacactaa 14120 14133 2-10-2 363_1 TAatcttacactAA  364ataatcttacacta 14121 14134 2-10-2 364_1 ATaatcttacacTA  365aataatcttacact 14122 14135 2-10-2 365_1 AAtaatcttacaCT  366gaataatcttacac 14123 14136 2-10-2 366_1 GAataatcttacAC  367tgaataatcttaca 14124 14137 2-10-2 367_1 TGaataatcttaCA  368atgaataatcttac 14125 14138 2-10-2 368_1 ATgaataatcttAC  369caaaattctaataa 14257 14270 2-10-2 369_1 CAaaattctaatAA  370tcaaaattctaata 14258 14271 2-10-2 370_1 TCaaaattctaaTA  371ttcaaaattctaat 14259 14272 2-10-2 371_1 TTcaaaattctaAT  372attcaaaattctaa 14260 14273 2-10-2 372_1 ATtcaaaattctAA  373gattcaaaattcta 14261 14274 2-10-2 373_1 GAttcaaaattcTA  374agattcaaaattct 14262 14275 2-10-2 374_1 AGattcaaaattCT  375attactacaaccaa 14570 14583 2-10-2 375_1 ATtactacaaccAA  376cattactacaacca 14571 14584 2-10-2 376_1 CAttactacaacCA  377ccattactacaacc 14572 14585 2-10-2 377_1 CCattactacaaCC  378accattactacaac 14573 14586 2-10-2 378_1 ACcattactacaAC  379aaccattactacaa 14574 14587 2-10-2 379_1 AAccattactacAA  380aaaccattactaca 14575 14588 2-10-2 380_1 AAaccattactaCA  381gaaaccattactac 14576 14589 2-10-2 381_1 GAaaccattactAC  382tgaaaccattacta 14577 14590 2-10-2 382_1 TGaaaccattacTA  383atgaaaccattact 14578 14591 2-10-2 383_1 ATgaaaccattaCT  384atttttaaaaacac 15778 15791 2-10-2 384_1 ATttttaaaaacAC  385aatttttaaaaaca 15779 15792 2-10-2 385_1 AAtttttaaaaaCA  386taatttttaaaaac 15780 15793 2-10-2 386_1 TAatttttaaaaAC  387ataatttttaaaaa 15781 15794 2-10-2 387_1 ATaatttttaaaAA  388cataatttttaaaa 15782 15795 2-10-2 388_1 CAtaatttttaaAA  389tcataatttttaaa 15783 15796 2-10-2 389_1 TCataatttttaAA  390atcataatttttaa 15784 15797 2-10-2 390_1 ATcataatttttAA  391ctttatacaaaaaa 15814 15827 2-10-2 391_1 CTttatacaaaaAA  392actttatacaaaaa 15815 15828 2-10-2 392_1 ACtttatacaaaAA  393tactttatacaaaa 15816 15829 2-10-2 393_1 TActttatacaaAA  394ttactttatacaaa 15817 15830 2-10-2 394_1 TTactttatacaAA  395cttactttatacaa 15818 15831 2-10-2 395_1 CTtactttatacAA  396gcttactttataca 15819 15832 2-10-2 396_1 GCttactttataCA  397tgcttactttatac 15820 15833 2-10-2 397_1 TGcttactttatAC  398tctcaaaataataa 15877 15890 2-10-2 398_1 TCtcaaaataatAA  399ctctcaaaataata 15878 15891 2-10-2 399_1 CTctcaaaataaTA  400tctctcaaaataat 15879 15892 2-10-2 400_1 TCtctcaaaataAT  401atctctcaaaataa 15880 15893 2-10-2 401_1 ATctctcaaaatAA  402aatctctcaaaata 15881 15894 2-10-2 402_1 AAtctctcaaaaTA  403aaatctctcaaaat 15882 15895 2-10-2 403_1 AAatctctcaaaAT  404taaatctctcaaaa 15883 15896 2-10-2 404_1 TAaatctctcaaAA  405ttaaatctctcaaa 15884 15897 2-10-2 405_1 TTaaatctctcaAA  406tttaaatctctcaa 15885 15898 2-10-2 406_1 TTtaaatctctcAA  407ttttaaatctctca 15886 15899 2-10-2 407_1 TTttaaatctctCA  408taatactttttcca 16080 16093 2-10-2 408_1 TAatactttttcCA  409ttaatactttttcc 16081 16094 2-10-2 409_1 TTaatactttttCC  410gttaatactttttc 16082 16095 2-10-2 410_1 GTtaatacttttTC  411tgttaatacttttt 16083 16096 2-10-2 411_1 TGttaatactttTT  412atgttaatactttt 16084 16097 2-10-2 412_1 ATgttaatacttTT  413ttatcactaccaca 16187 16200 2-10-2 413_1 TTatcactaccaCA  414tttatcactaccac 16188 16201 2-10-2 414_1 TTtatcactaccAC  415atttatcactacca 16189 16202 2-10-2 415_1 ATttatcactacCA  416catttatcactacc 16190 16203 2-10-2 416_1 CAtttatcactaCC  417tcatttatcactac 16191 16204 2-10-2 417_1 TCatttatcactAC  418atcatttatcacta 16192 16205 2-10-2 418_1 ATcatttatcacTA  419catcatttatcact 16193 16206 2-10-2 419_1 CAtcatttatcaCT  420acatcatttatcac 16194 16207 2-10-2 420_1 ACatcatttatcAC  421aacatcatttatca 16195 16208 2-10-2 421_1 AAcatcatttatCA  422taacatcatttatc 16196 16209 2-10-2 422_1 TAacatcatttaTC  423ttaacatcatttat 16197 16210 2-10-2 423_1 TTaacatcatttAT  424attaacatcattta 16198 16211 2-10-2 424_1 ATtaacatcattTA  425aattaacatcattt 16199 16212 2-10-2 425_1 AAttaacatcatTT  426taattaacatcatt 16200 16213 2-10-2 426_1 TAattaacatcaTT  427ctaattaacatcat 16201 16214 2-10-2 427_1 CTaattaacatcAT  428cctaattaacatca 16202 16215 2-10-2 428_1 CCtaattaacatCA  429ccctaattaacatc 16203 16216 2-10-2 429_1 CCctaattaacaTC  430gccctaattaacat 16204 16217 2-10-2 430_1 GCcctaattaacAT  431ggccctaattaaca 16205 16218 2-10-2 431_1 GGccctaattaaCA  432cggccctaattaac 16206 16219 2-10-2 432_1 CGgccctaattaAC  433aaacacattttttt 16494 16507 2-10-2 433_1 AAacacatttttTT  434taaacacatttttt 16495 16508 2-10-2 434_1 TAaacacattttTT  435ataaacacattttt 16496 16509 2-10-2 435_1 ATaaacacatttTT  436tataaacacatttt 16497 16510 2-10-2 436_1 TAtaaacacattTT  437atataaacacattt 16498 16511 2-10-2 437_1 ATataaacacatTT  438catataaacacatt 16499 16512 2-10-2 438_1 CAtataaacacaTT  439acatataaacacat 16500 16513 2-10-2 439_1 ACatataaacacAT  440aacatataaacaca 16501 16514 2-10-2 440_1 AAcatataaacaCA  441taacatataaacac 16502 16515 2-10-2 441_1 TAacatataaacAC  442ataacatataaaca 16503 16516 2-10-2 442_1 ATaacatataaaCA  443tataacatataaac 16504 16517 2-10-2 443_1 TAtaacatataaAC  444atataacatataaa 16505 16518 2-10-2 444_1 ATataacatataAA  445catataacatataa 16506 16519 2-10-2 445_1 CAtataacatatAA  446acatataacatata 16507 16520 2-10-2 446_1 ACatataacataTA  447cacatataacatat 16508 16521 2-10-2 447_1 CAcatataacatAT  448tcacatataacata 16509 16522 2-10-2 448_1 TCacatataacaTA  449atcacatataacat 16510 16523 2-10-2 449_1 ATcacatataacAT  450tatcacatataaca 16511 16524 2-10-2 450_1 TAtcacatataaCA  451ctatcacatataac 16512 16525 2-10-2 451_1 CTatcacatataAC  452actatcacatataa 16513 16526 2-10-2 452_1 ACtatcacatatAA  453cactatcacatata 16514 16527 2-10-2 453_1 CActatcacataTA  454gtccaacataactc 16834 16847 2-10-2 454_1 GTccaacataacTC  455agtccaacataact 16835 16848 2-10-2 455_1 AGtccaacataaCT  456cagtccaacataac 16836 16849 2-10-2 456_1 CAgtccaacataAC  457tcagtccaacataa 16837 16850 2-10-2 457_1 TCagtccaacatAA  458atcagtccaacata 16838 16851 2-10-2 458_1 ATcagtccaacaTA  459tatcagtccaacat 16839 16852 2-10-2 459_1 TAtcagtccaacAT  460aaaccctcccaaaa 16921 16934 2-10-2 460_1 AAaccctcccaaAA  461taaaccctcccaaa 16922 16935 2-10-2 461_1 TAaaccctcccaAA  462ttaaaccctcccaa 16923 16936 2-10-2 462_1 TTaaaccctcccAA  463attaaaccctccca 16924 16937 2-10-2 463_1 ATtaaaccctccCA  464cattaaaccctccc 16925 16938 2-10-2 464_1 CAttaaaccctcCC  465acattaaaccctcc 16926 16939 2-10-2 465_1 ACattaaaccctCC  466aacattaaaccctc 16927 16940 2-10-2 466_1 AAcattaaacccTC  467aaacattaaaccct 16928 16941 2-10-2 467_1 AAacattaaaccCT  468taaacattaaaccc 16929 16942 2-10-2 468_1 TAaacattaaacCC  469ataaacattaaacc 16930 16943 2-10-2 469_1 ATaaacattaaaCC  470tataaacattaaac 16931 16944 2-10-2 470_1 TAtaaacattaaAC  471ctataaacattaaa 16932 16945 2-10-2 471_1 CTataaacattaAA  472actataaacattaa 16933 16946 2-10-2 472_1 ACtataaacattAA  473aactataaacatta 16934 16947 2-10-2 473_1 AActataaacatTA  474aaactataaacatt 16935 16948 2-10-2 474_1 AAactataaacaTT  475taaactataaacat 16936 16949 2-10-2 475_1 TAaactataaacAT  476ttaaactataaaca 16937 16950 2-10-2 476_1 TTaaactataaaCA  477tttaaactataaac 16938 16951 2-10-2 477_1 TTtaaactataaAC  478ctttaaactataaa 16939 16952 2-10-2 478_1 CTttaaactataAA  479gctttaaactataa 16940 16953 2-10-2 479_1 GCtttaaactatAA  480tgctttaaactata 16941 16954 2-10-2 480_1 TGctttaaactaTA  481cagcctatcaccac 18018 18031 2-10-2 481_1 CAgcctatcaccAC  482acagcctatcacca 18019 18032 2-10-2 482_1 ACagcctatcacCA  483cacagcctatcacc 18020 18033 2-10-2 483_1 CAcagcctatcaCC  484tcacagcctatcac 18021 18034 2-10-2 484_1 TCacagcctatcAC  485atcacagcctatca 18022 18035 2-10-2 485_1 ATcacagcctatCA  486aatcacagcctatc 18023 18036 2-10-2 486_1 AAtcacagcctaTC  487aaatcacagcctat 18024 18037 2-10-2 487_1 AAatcacagcctAT  488caaatcacagccta 18025 18038 2-10-2 488_1 CAaatcacagccTA  489ccaaatcacagcct 18026 18039 2-10-2 489_1 CCaaatcacagcCT  490cccaaatcacagcc 18027 18040 2-10-2 490_1 CCcaaatcacagCC  491acccaaatcacagc 18028 18041 2-10-2 491_1 ACccaaatcacaGC  492cacccaaatcacag 18029 18042 2-10-2 492_1 CAcccaaatcacAG  493tcacccaaatcaca 18030 18043 2-10-2 493_1 TCacccaaatcaCA  494gtcacccaaatcac 18031 18044 2-10-2 494_1 GTcacccaaatcAC  495cgtcacccaaatca 18032 18045 2-10-2 495_1 CGtcacccaaatCA  496gcgtcacccaaatc 18033 18046 2-10-2 496_1 GCgtcacccaaaTC  497agcgtcacccaaat 18034 18047 2-10-2 497_1 AGcgtcacccaaAT  498atcctaaaatcact 18630 18643 2-10-2 498_1 ATcctaaaatcaCT  499gatcctaaaatcac 18631 18644 2-10-2 499_1 GAtcctaaaatcAC  500agatcctaaaatca 18632 18645 2-10-2 500_1 AGatcctaaaatCA  501cagatcctaaaatc 18633 18646 2-10-2 501_1 CAgatcctaaaaTC  502tcagatcctaaaat 18634 18647 2-10-2 502_1 TCagatcctaaaAT  503aaaccaatcatcat 19107 19120 2-10-2 503_1 AAaccaatcatcAT  504aaaaccaatcatca 19108 19121 2-10-2 504_1 AAaaccaatcatCA  505taaaaccaatcatc 19109 19122 2-10-2 505_1 TAaaaccaatcaTC  506gtaaaaccaatcat 19110 19123 2-10-2 506_1 GTaaaaccaatcAT  507agtaaaaccaatca 19111 19124 2-10-2 507_1 AGtaaaaccaatCA  508aagtaaaaccaatc 19112 19125 2-10-2 508_1 AAgtaaaaccaaTC  509aaagtaaaaccaat 19113 19126 2-10-2 509_1 AAagtaaaaccaAT  510catctctactaaaa 20214 20227 2-10-2 510_1 CAtctctactaaAA  511ccatctctactaaa 20215 20228 2-10-2 511_1 CCatctctactaAA  512tccatctctactaa 20216 20229 2-10-2 512_1 TCcatctctactAA  513ttccatctctacta 20217 20230 2-10-2 513_1 TTccatctctacTA  514cttccatctctact 20218 20231 2-10-2 514_1 CTtccatctctaCT  515ccttccatctctac 20219 20232 2-10-2 515_1 CCttccatctctAC  516cccttccatctcta 20220 20233 2-10-2 516_1 CCcttccatctcTA  517acataacaaaccca 20555 20568 2-10-2 517_1 ACataacaaaccCA  518tacataacaaaccc 20556 20569 2-10-2 518_1 TAcataacaaacCC  519ctacataacaaacc 20557 20570 2-10-2 519_1 CTacataacaaaCC  520actacataacaaac 20558 20571 2-10-2 520_1 ACtacataacaaAC  521aactacataacaaa 20559 20572 2-10-2 521_1 AActacataacaAA  522taactacataacaa 20560 20573 2-10-2 522_1 TAactacataacAA  523ataactacataaca 20561 20574 2-10-2 523_1 ATaactacataaCA  524aataactacataac 20562 20575 2-10-2 524_1 AAtaactacataAC  525caataactacataa 20563 20576 2-10-2 525_1 CAataactacatAA  526acaataactacata 20564 20577 2-10-2 526_1 ACaataactacaTA  527cacaataactacat 20565 20578 2-10-2 527_1 CAcaataactacAT  528tcacaataactaca 20566 20579 2-10-2 528_1 TCacaataactaCA  529ttcacaataactac 20567 20580 2-10-2 529_1 TTcacaataactAC  530attcacaataacta 20568 20581 2-10-2 530_1 ATtcacaataacTA  531aattcacaataact 20569 20582 2-10-2 531_1 AAttcacaataaCT  532gaattcacaataac 20570 20583 2-10-2 532_1 GAattcacaataAC  533tgaattcacaataa 20571 20584 2-10-2 533_1 TGaattcacaatAA  534ctaaaacaatctaa 22073 22086 2-10-2 534_1 CTaaaacaatctAA  535cctaaaacaatcta 22074 22087 2-10-2 535_1 CCtaaaacaatcTA  536acctaaaacaatct 22075 22088 2-10-2 536_1 ACctaaaacaatCT  537tacctaaaacaatc 22076 22089 2-10-2 537_1 TAcctaaaacaaTC  538atacctaaaacaat 22077 22090 2-10-2 538_1 ATacctaaaacaAT  539tatacctaaaacaa 22078 22091 2-10-2 539_1 TAtacctaaaacAA  540ctatacctaaaaca 22079 22092 2-10-2 540_1 CTatacctaaaaCA  541gctatacctaaaac 22080 22093 2-10-2 541_1 GCtatacctaaaAC  542ttgtaactaaaaat 22254 22267 2-10-2 542_1 TTgtaactaaaaAT  543cttgtaactaaaaa 22255 22268 2-10-2 543_1 CTtgtaactaaaAA  544ccttgtaactaaaa 22256 22269 2-10-2 544_1 CCttgtaactaaAA  545cccttgtaactaaa 22257 22270 2-10-2 545_1 CCcttgtaactaAA  546ccccttgtaactaa 22258 22271 2-10-2 546_1 CCccttgtaactAA  547accccttgtaacta 22259 22272 2-10-2 547_1 ACcccttgtaacTA  548caccccttgtaact 22260 22273 2-10-2 548_1 CAccccttgtaaCT  549acaccccttgtaac 22261 22274 2-10-2 549_1 ACaccccttgtaAC  550ttcatatatacatc 22424 22437 2-10-2 550_1 TTcatatatacaTC  551cttcatatatacat 22425 22438 2-10-2 551_1 CTtcatatatacAT  552ccttcatatataca 22426 22439 2-10-2 552_1 CCttcatatataCA  553cccttcatatatac 22427 22440 2-10-2 553_1 CCcttcatatatAC  554acccttcatatata 22428 22441 2-10-2 554_1 ACccttcatataTA  555tacccttcatatat 22429 22442 2-10-2 555_1 TAcccttcatatAT  556ttacccttcatata 22430 22443 2-10-2 556_1 TTacccttcataTA  557attacccttcatat 22431 22444 2-10-2 557_1 ATtacccttcatAT  558cattacccttcata 22432 22445 2-10-2 558_1 CAttacccttcaTA  559acattacccttcat 22433 22446 2-10-2 559_1 ACattacccttcAT  560tacattacccttca 22434 22447 2-10-2 560_1 TAcattacccttCA  561tcttatacttacta 23204 23217 2-10-2 561_1 TCttatacttacTA  562ttcttatacttact 23205 23218 2-10-2 562_1 TTcttatacttaCT  563attcttatacttac 23206 23219 2-10-2 563_1 ATtcttatacttAC  564gattcttatactta 23207 23220 2-10-2 564_1 GAttcttatactTA  565tgattcttatactt 23208 23221 2-10-2 565_1 TGattcttatacTT  566atgattcttatact 23209 23222 2-10-2 566_1 ATgattcttataCT  567aacttcactaaaat 23616 23629 2-10-2 567_1 AActtcactaaaAT  568aaacttcactaaaa 23617 23630 2-10-2 568_1 AAacttcactaaAA  569taaacttcactaaa 23618 23631 2-10-2 569_1 TAaacttcactaAA  570ataaacttcactaa 23619 23632 2-10-2 570_1 ATaaacttcactAA  571aataaacttcacta 23620 23633 2-10-2 571_1 AAtaaacttcacTA  572taataaacttcact 23621 23634 2-10-2 572_1 TAataaacttcaCT  573ctaataaacttcac 23622 23635 2-10-2 573_1 CTaataaacttcAC  574actaataaacttca 23623 23636 2-10-2 574_1 ACtaataaacttCA  575aactaataaacttc 23624 23637 2-10-2 575_1 AActaataaactTC  576aatcttctatttta 24108 24121 2-10-2 576_1 AAtcttctatttTA  577caatcttctatttt 24109 24122 2-10-2 577_1 CAatcttctattTT  578ccaatcttctattt 24110 24123 2-10-2 578_1 CCaatcttctatTT  579accaatcttctatt 24111 24124 2-10-2 579_1 ACcaatcttctaTT  580aaccaatcttctat 24112 24125 2-10-2 580_1 AAccaatcttctAT  581caaccaatcttcta 24113 24126 2-10-2 581_1 CAaccaatcttcTA  582gcaaccaatcttct 24114 24127 2-10-2 582_1 GCaaccaatcttCT  583tgcaaccaatcttc 24115 24128 2-10-2 583_1 TGcaaccaatctTC  584ctgcaaccaatctt 24116 24129 2-10-2 584_1 CTgcaaccaatcTT  585actgcaaccaatct 24117 24130 2-10-2 585_1 ACtgcaaccaatCT  586aactgcaaccaatc 24118 24131 2-10-2 586_1 AActgcaaccaaTC  587taactgcaaccaat 24119 24132 2-10-2 587_1 TAactgcaaccaAT  588tacaacacacatca 24335 24348 2-10-2 588_1 TAcaacacacatCA  589atacaacacacatc 24336 24349 2-10-2 589_1 ATacaacacacaTC  590aatacaacacacat 24337 24350 2-10-2 590_1 AAtacaacacacAT  591gaatacaacacaca 24338 24351 2-10-2 591_1 GAatacaacacaCA  592tgaatacaacacac 24339 24352 2-10-2 592_1 TGaatacaacacAC  593atgaatacaacaca 24340 24353 2-10-2 593_1 ATgaatacaacaCA  594cctaataaaatata 24499 24512 2-10-2 594_1 CCtaataaaataTA  595tcctaataaaatat 24500 24513 2-10-2 595_1 TCctaataaaatAT  596ctcctaataaaata 24501 24514 2-10-2 596_1 CTcctaataaaaTA  597actcctaataaaat 24502 24515 2-10-2 597_1 ACtcctaataaaAT  598tactcctaataaaa 24503 24516 2-10-2 598_1 TActcctaataaAA  599ctactcctaataaa 24504 24517 2-10-2 599_1 CTactcctaataAA  600actactcctaataa 24505 24518 2-10-2 600_1 ACtactcctaatAA  601aactactcctaata 24506 24519 2-10-2 601_1 AActactcctaaTA  602taactactcctaat 24507 24520 2-10-2 602_1 TAactactcctaAT  603ataactactcctaa 24508 24521 2-10-2 603_1 ATaactactcctAA  604tataactactccta 24509 24522 2-10-2 604_1 TAtaactactccTA  605atataactactcct 24510 24523 2-10-2 605_1 ATataactactcCT  606aatataactactcc 24511 24524 2-10-2 606_1 AAtataactactCC  607aaatataactactc 24512 24525 2-10-2 607_1 AAatataactacTC  608aaaatataactact 24513 24526 2-10-2 608_1 AAaatataactaCT  609aaaaatataactac 24514 24527 2-10-2 609_1 AAaaatataactAC  610taaaaatataacta 24515 24528 2-10-2 610_1 TAaaaatataacTA  611gtaaaaatataact 24516 24529 2-10-2 611_1 GTaaaaatataaCT  612agtaaaaatataac 24517 24530 2-10-2 612_1 AGtaaaaatataAC  613actgatacccacaa 24593 24606 2-10-2 613_1 ACtgatacccacAA  614aactgatacccaca 24594 24607 2-10-2 614_1 AActgatacccaCA  615caactgatacccac 24595 24608 2-10-2 615_1 CAactgatacccAC  616tcaactgataccca 24596 24609 2-10-2 616_1 TCaactgataccCA  617atcactaaaaaact 24752 24765 2-10-2 617_1 ATcactaaaaaaCT  618tatcactaaaaaac 24753 24766 2-10-2 618_1 TAtcactaaaaaAC  619atatcactaaaaaa 24754 24767 2-10-2 619_1 ATatcactaaaaAA  620tatatcactaaaaa 24755 24768 2-10-2 620_1 TAtatcactaaaAA  621ttatatcactaaaa 24756 24769 2-10-2 621_1 TTatatcactaaAA  622tttatatcactaaa 24757 24770 2-10-2 622_1 TTtatatcactaAA  623gtttatatcactaa 24758 24771 2-10-2 623_1 GTttatatcactAA  624aaacttttaattaa 24850 24863 2-10-2 624_1 AAacttttaattAA  625caaacttttaatta 24851 24864 2-10-2 625_1 CAaacttttaatTA  626tcaaacttttaatt 24852 24865 2-10-2 626_1 TCaaacttttaaTT  627ttcaaacttttaat 24853 24866 2-10-2 627_1 TTcaaacttttaAT  628cttcaaacttttaa 24854 24867 2-10-2 628_1 CTtcaaacttttAA  629acttcaaactttta 24855 24868 2-10-2 629_1 ACttcaaactttTA  630cacttcaaactttt 24856 24869 2-10-2 630_1 CActtcaaacttTT  631ccacttcaaacttt 24857 24870 2-10-2 631_1 CCacttcaaactTT  632cccacttcaaactt 24858 24871 2-10-2 632_1 CCcacttcaaacTT  633acccacttcaaact 24859 24872 2-10-2 633_1 ACccacttcaaaCT  634aacccacttcaaac 24860 24873 2-10-2 634_1 AAcccacttcaaAC  635aaacccacttcaaa 24861 24874 2-10-2 635_1 AAacccacttcaAA  636aaaacccacttcaa 24862 24875 2-10-2 636_1 AAaacccacttcAA  637aaaaacccacttca 24863 24876 2-10-2 637_1 AAaaacccacttCA  638aaaaaacccacttc 24864 24877 2-10-2 638_1 AAaaaacccactTC  639caaaaaacccactt 24865 24878 2-10-2 639_1 CAaaaaacccacTT  640acaaaaaacccact 24866 24879 2-10-2 640_1 ACaaaaaacccaCT  641aacaaaaaacccac 24867 24880 2-10-2 641_1 AAcaaaaaacccAC  642aaacaaaaaaccca 24868 24881 2-10-2 642_1 AAacaaaaaaccCA  643aaaacaaaaaaccc 24869 24882 2-10-2 643_1 AAaacaaaaaacCC  644atcttcccattaat 24976 24989 2-10-2 644_1 ATcttcccattaAT  645aatcttcccattaa 24977 24990 2-10-2 645_1 AAtcttcccattAA  646taatcttcccatta 24978 24991 2-10-2 646_1 TAatcttcccatTA  647ataatcttcccatt 24979 24992 2-10-2 647_1 ATaatcttcccaTT  648aataatcttcccat 24980 24993 2-10-2 648_1 AAtaatcttcccAT  649aaataatcttccca 24981 24994 2-10-2 649_1 AAataatcttccCA  650aaaataatcttccc 24982 24995 2-10-2 650_1 AAaataatcttcCC  651tattaatcaaaaat 25057 25070 2-10-2 651_1 TAttaatcaaaaAT  652ctattaatcaaaaa 25058 25071 2-10-2 652_1 CTattaatcaaaAA  653tctattaatcaaaa 25059 25072 2-10-2 653_1 TCtattaatcaaAA  654ctctattaatcaaa 25060 25073 2-10-2 654_1 CTctattaatcaAA  655actctattaatcaa 25061 25074 2-10-2 655_1 ACtctattaatcAA  656gactctattaatca 25062 25075 2-10-2 656_1 GActctattaatCA  657tattctactcttct 25433 25446 2-10-2 657_1 TAttctactcttCT  658atattctactcttc 25434 25447 2-10-2 658_1 ATattctactctTC  659aatattctactctt 25435 25448 2-10-2 659_1 AAtattctactcTT  660gaatattctactct 25436 25449 2-10-2 660_1 GAatattctactCT  661agaatattctactc 25437 25450 2-10-2 661_1 AGaatattctacTC  662atttaccaattcaa 25508 25521 2-10-2 662_1 ATttaccaattcAA  663tatttaccaattca 25509 25522 2-10-2 663_1 TAtttaccaattCA  664gtatttaccaattc 25510 25523 2-10-2 664_1 GTatttaccaatTC  665tgtatttaccaatt 25511 25524 2-10-2 665_1 TGtatttaccaaTT  666ctgtatttaccaat 25512 25525 2-10-2 666_1 CTgtatttaccaAT  667actgtatttaccaa 25513 25526 2-10-2 667_1 ACtgtatttaccAA  668ttataccatcaaat 27100 27113 2-10-2 668_1 TTataccatcaaAT  669attataccatcaaa 27101 27114 2-10-2 669_1 ATtataccatcaAA  670cattataccatcaa 27102 27115 2-10-2 670_1 CAttataccatcAA  671tcattataccatca 27103 27116 2-10-2 671_1 TCattataccatCA  672ttcattataccatc 27104 27117 2-10-2 672_1 TTcattataccaTC  673cttcattataccat 27105 27118 2-10-2 673_1 CTtcattataccAT  674tcttcattatacca 27106 27119 2-10-2 674_1 TCttcattatacCA  675ttcttcattatacc 27107 27120 2-10-2 675_1 TTcttcattataCC  676tttcttcattatac 27108 27121 2-10-2 676_1 TTtcttcattatAC  677ttttcttcattata 27109 27122 2-10-2 677_1 TTttcttcattaTA  678attttcttcattat 27110 27123 2-10-2 678_1 ATtttcttcattAT  679tattttcttcatta 27111 27124 2-10-2 679_1 TAttttcttcatTA  680atattttcttcatt 27112 27125 2-10-2 680_1 ATattttcttcaTT  681aatattttcttcat 27113 27126 2-10-2 681_1 AAattttcttcaAT  682aaatattttcttca 27114 27127 2-10-2 682_1 AAatattttcttCA  683taaatattttcttc 27115 27128 2-10-2 683_1 TAaatattttctTC  684aataatccaaactt 27772 27785 2-10-2 684_1 AAtaatccaaacTT  685aaataatccaaact 27773 27786 2-10-2 685_1 AAataatccaaaCT  686aaaataatccaaac 27774 27787 2-10-2 686_1 AAaataatccaaAC  687caaaataatccaaa 27775 27788 2-10-2 687_1 CAaaataatccaAA  688acaaaataatccaa 27776 27789 2-10-2 688_1 ACaaaataatccAA  689tacaaaataatcca 27777 27790 2-10-2 689_1 TAcaaaataatcCA  690ttacaaaataatcc 27778 27791 2-10-2 690_1 TTacaaaataatCC  691gttacaaaataatc 27779 27792 2-10-2 691_1 GTtacaaaataaTC  692tgttacaaaataat 27780 27793 2-10-2 692_1 TGttacaaaataAT  693ttttacattaacta 27935 27948 2-10-2 693_1 TTttacattaacTA  694tttttacattaact 27936 27949 2-10-2 694_1 TTtttacattaaCT  695ttttttacattaac 27937 27950 2-10-2 695_1 TTttttacattaAC  696attttttacattaa 27938 27951 2-10-2 696_1 ATtttttacattAA  697tattttttacatta 27939 27952 2-10-2 697_1 TAttttttacatTA  698ttattttttacatt 27940 27953 2-10-2 698_1 TTattttttacaTT  699aaatactaacatca 29299 29312 2-10-2 699_1 AAatactaacatCA  700aaaatactaacatc 29300 29313 2-10-2 700_1 AAaatactaacaTC  701caaaatactaacat 29301 29314 2-10-2 701_1 CAaaatactaacAT  702ccaaaatactaaca 29302 29315 2-10-2 702_1 CCaaaatactaaCA  703gccaaaatactaac 29303 29316 2-10-2 703_1 GCcaaaatactaAC  704tgccaaaatactaa 29304 29317 2-10-2 704_1 TGccaaaatactAA  705tccattcattttat 29415 29428 2-10-2 705_1 TCcattcattttAT  706atccattcatttta 29416 29429 2-10-2 706_1 ATccattcatttTA  707catccattcatttt 29417 29430 2-10-2 707_1 CAtccattcattTT  708acatccattcattt 29418 29431 2-10-2 708_1 ACatccattcatTT  709cacatccattcatt 29419 29432 2-10-2 709_1 CAcatccattcaTT  710ccacatccattcat 29420 29433 2-10-2 710_1 CCacatccattcAT  711gccacatccattca 29421 29434 2-10-2 711_1 GCcacatccattCA  712tgccacatccattc 29422 29435 2-10-2 712_1 TGccacatccatTC  713atgccacatccatt 29423 29436 2-10-2 713_1 ATgccacatccaTT  714tatgccacatccat 29424 29437 2-10-2 714_1 TAtgccacatccAT  715ttatgccacatcca 29425 29438 2-10-2 715_1 TTatgccacatcCA  716attatgccacatcc 29426 29439 2-10-2 716_1 ATtatgccacatCC  717tcttaactcttctc 30753 30766 2-10-2 717_1 TCttaactcttcTC  718ttcttaactcttct 30754 30767 2-10-2 718_1 TTcttaactcttCT  719gttcttaactcttc 30755 30768 2-10-2 719_1 GTtcttaactctTC  720agttcttaactctt 30756 30769 2-10-2 720_1 AGttcttaactcTT  721tagttcttaactct 30757 30770 2-10-2 721_1 TAgttcttaactCT  722caaatactcaaaaa 31029 31042 2-10-2 722_1 CAaatactcaaaAA  723tcaaatactcaaaa 31030 31043 2-10-2 723_1 TCaaatactcaaAA  724ttcaaatactcaaa 31031 31044 2-10-2 724_1 TTcaaatactcaAA  725cttcaaatactcaa 31032 31045 2-10-2 725_1 CTtcaaatactcAA  726gcttcaaatactca 31033 31046 2-10-2 726_1 GCttcaaatactCA  727agcttcaaatactc 31034 31047 2-10-2 727_1 AGcttcaaatacTC  728aagcttcaaatact 31035 31048 2-10-2 728_1 AAgcttcaaataCT  729cctcattacccatt 32059 32072 2-10-2 729_1 CCtcattacccaTT  730tcctcattacccat 32060 32073 2-10-2 730_1 TCctcattacccAT  731atcctcattaccca 32061 32074 2-10-2 731_1 ATcctcattaccCA  732tatcctcattaccc 32062 32075 2-10-2 732_1 TAtcctcattacCC  733atatcctcattacc 32063 32076 2-10-2 733_1 ATatcctcattaCC  734aatatcctcattac 32064 32077 2-10-2 734_1 AAtatcctcattAC  735taatatcctcatta 32065 32078 2-10-2 735_1 TAatatcctcatTA  736ttaatatcctcatt 32066 32079 2-10-2 736_1 TTaatatcctcaTT  737tttaatatcctcat 32067 32080 2-10-2 737_1 TTtaatatcctcAT  738atttaatatcctca 32068 32081 2-10-2 738_1 ATttaatatcctCA  739aatttaatatcctc 32069 32082 2-10-2 739_1 AAtttaatatccTC  740aaatttaatatcct 32070 32083 2-10-2 740_1 AAatttaatatcCT  741taaatttaatatcc 32071 32084 2-10-2 741_1 TAaatttaatatCC  742ttaaatttaatatc 32072 32085 2-10-2 742_1 TTaaatttaataTC  743cttaaatttaatat 32073 32086 2-10-2 743_1 CTtaaatttaatAT  744tcttaaatttaata 32074 32087 2-10-2 744_1 TCttaaatttaaTA  745ttcttaaatttaat 32075 32088 2-10-2 745_1 TTcttaaatttaAT  746gttcttaaatttaa 32076 32089 2-10-2 746_1 GTtcttaaatttAA  747ttattctactttta 33431 33444 2-10-2 747_1 TTattctactttTA  748tttattctactttt 33432 33445 2-10-2 748_1 TTtattctacttTT  749ctttattctacttt 33433 33446 2-10-2 749_1 CTttattctactTT  750cctttattctactt 33434 33447 2-10-2 750_1 CCtttattctacTT  751gcctttattctact 33435 33448 2-10-2 751_1 GCctttattctaCT  752aacaattattaata 33797 33810 2-10-2 752_1 AAcaattattaaTA  753caacaattattaat 33798 33811 2-10-2 753_1 CAacaattattaAT  754gcaacaattattaa 33799 33812 2-10-2 754_1 GCaacaattattAA  755agcaacaattatta 33800 33813 2-10-2 755_1 AGcaacaattatTA  756cagcaacaattatt 33801 33814 2-10-2 756_1 CAgcaacaattaTT  757ccagcaacaattat 33802 33815 2-10-2 757_1 CCagcaacaattAT  758accagcaacaatta 33803 33816 2-10-2 758_1 ACcagcaacaatTA  759aaaccaaaacttac 33963 33976 2-10-2 759_1 AAaccaaaacttAC  760aaaaccaaaactta 33964 33977 2-10-2 760_1 AAaaccaaaactTA  761aaaaaccaaaactt 33965 33978 2-10-2 761_1 AAaaaccaaaacTT  762caaaaaccaaaact 33966 33979 2-10-2 762_1 CAaaaaccaaaaCT  763ccaaaaaccaaaac 33967 33980 2-10-2 763_1 CCaaaaaccaaaAC  764accaaaaaccaaaa 33968 33981 2-10-2 764_1 ACcaaaaaccaaAA  765aaccaaaaaccaaa 33969 33982 2-10-2 765_1 AAccaaaaaccaAA  766aaaccaaaaaccaa 33970 33983 2-10-2 766_1 AAaccaaaaaccAA  767atctaaaacacttc 34050 34063 2-10-2 767_1 ATctaaaacactTC  768aatctaaaacactt 34051 34064 2-10-2 768_1 AAtctaaaacacTT  769aaatctaaaacact 34052 34065 2-10-2 769_1 AAatctaaaacaCT  770caaatctaaaacac 34053 34066 2-10-2 770_1 CAaatctaaaacAC  771ccaaatctaaaaca 34054 34067 2-10-2 771_1 CCaaatctaaaaCA  772cccaaatctaaaac 34055 34068 2-10-2 772_1 CCcaaatctaaaAC  773ccccaaatctaaaa 34056 34069 2-10-2 773_1 CCccaaatctaaAA  774accccaaatctaaa 34057 34070 2-10-2 774_1 ACcccaaatctaAA  775aaccccaaatctaa 34058 34071 2-10-2 775_1 AAccccaaatctAA  776aaaccccaaatcta 34059 34072 2-10-2 776_1 AAaccccaaatcTA  777attcacaaatccta 34075 34088 2-10-2 777_1 ATtcacaaatccTA  778tattcacaaatcct 34076 34089 2-10-2 778_1 TAttcacaaatcCT  779atattcacaaatcc 34077 34090 2-10-2 779_1 ATattcacaaatCC  780aatattcacaaatc 34078 34091 2-10-2 780_1 AAtattcacaaaTC  781aaatattcacaaat 34079 34092 2-10-2 781_1 AAatattcacaaAT  782caaatattcacaaa 34080 34093 2-10-2 782_1 CAaatattcacaAA  783gcaaatattcacaa 34081 34094 2-10-2 783_1 GCaaatattcacAA  784aacacacattatca 34537 34550 2-10-2 784_1 AAcacacattatCA  785taacacacattatc 34538 34551 2-10-2 785_1 TAacacacattaTC  786ttaacacacattat 34539 34552 2-10-2 786_1 TTaacacacattAT  787tttaacacacatta 34540 34553 2-10-2 787_1 TTtaacacacatTA  788atttaacacacatt 34541 34554 2-10-2 788_1 ATttaacacacaTT  789tatttaacacacat 34542 34555 2-10-2 789_1 TAtttaacacacAT  790ctatttaacacaca 34543 34556 2-10-2 790_1 CTatttaacacaCA  791actatttaacacac 34544 34557 2-10-2 791_1 ACtatttaacacAC  792tactatttaacaca 34545 34558 2-10-2 792_1 TActatttaacaCA  793ctactatttaacac 34546 34559 2-10-2 793_1 CTactatttaacAC  794actactatttaaca 34547 34560 2-10-2 794_1 ACtactatttaaCA  795aactactatttaac 34548 34561 2-10-2 795_1 AActactatttaAC  796aaactactatttaa 34549 34562 2-10-2 796_1 AAactactatttAA  797aaaactactattta 34550 34563 2-10-2 797_1 AAaactactattTA  798gaaaactactattt 34551 34564 2-10-2 798_1 GAaaactactatTT  799tgaaaactactatt 34552 34565 2-10-2 799_1 TGaaaactactaTT  800aaataacctatcat 35309 35322 2-10-2 800_1 AAataacctatcAT  801aaaataacctatca 35310 35323 2-10-2 801_1 AAaataacctatCA  802caaaataacctatc 35311 35324 2-10-2 802_1 CAaaataacctaTC  803acaaaataacctat 35312 35325 2-10-2 803_1 ACaaaataacctAT  804cacaaaataaccta 35313 35326 2-10-2 804_1 CAcaaaataaccTA  805tcacaaaataacct 35314 35327 2-10-2 805_1 TCacaaaataacCT  806atcacaaaataacc 35315 35328 2-10-2 806_1 ATcacaaaataaCC  807catcacaaaataac 35316 35329 2-10-2 807_1 CAtcacaaaataAC  808tcatcacaaaataa 35317 35330 2-10-2 808_1 TCatcacaaaatAA  809ttcatcacaaaata 35318 35331 2-10-2 809_1 TTcatcacaaaaTA  810tttcatcacaaaat 35319 35332 2-10-2 810_1 TTtcatcacaaaAT  811ttttcatcacaaaa 35320 35333 2-10-2 811_1 TTttcatcacaaAA  812attttcatcacaaa 35321 35334 2-10-2 812_1 ATtttcatcacaAA  813tattttcatcacaa 35322 35335 2-10-2 813_1 TAttttcatcacAA  814gtattttcatcaca 35323 35336 2-10-2 814_1 GTattttcatcaCA  815atttaaatttatca 35354 35367 2-10-2 815_1 ATttaaatttatCA  816aatttaaatttatc 35355 35368 2-10-2 816_1 AAtttaaatttaTC  817aaatttaaatttat 35356 35369 2-10-2 817_1 AAatttaaatttAT  818aaaatttaaattta 35357 35370 2-10-2 818_1 AAaatttaaattTA  819taaaatttaaattt 35358 35371 2-10-2 819_1 TAaaatttaaatTT  820ataaaatttaaatt 35359 35372 2-10-2 820_1 ATaaaatttaaaTT  821cataaaatttaaat 35360 35373 2-10-2 821_1 CAtaaaatttaaAT  822acataaaatttaaa 35361 35374 2-10-2 822_1 ACataaaatttaAA  823ctactaatattcat 36332 36345 2-10-2 823_1 CTactaatattcAT  824cctactaatattca 36333 36346 2-10-2 824_1 CCtactaatattCA  825acctactaatattc 36334 36347 2-10-2 825_1 ACctactaatatTC  826cacctactaatatt 36335 36348 2-10-2 826_1 CAcctactaataTT  827tcacctactaatat 36336 36349 2-10-2 827_1 TCacctactaatAT  828ttcacctactaata 36337 36350 2-10-2 828_1 TTcacctactaaTA  829tttcacctactaat 36338 36351 2-10-2 829_1 TTtcacctactaAT  830ttttcacctactaa 36339 36352 2-10-2 830_1 TTttcacctactAA  831tttttcacctacta 36340 36353 2-10-2 831_1 TTtttcacctacTA  832atttttcacctact 36341 36354 2-10-2 832_1 ATttttcacctaCT  833tatttttcacctac 36342 36355 2-10-2 833_1 TAtttttcacctAC  834ttatttttcaccta 36343 36356 2-10-2 834_1 TTatttttcaccTA  835tttatttttcacct 36344 36357 2-10-2 835_1 TTtatttttcacCT  836ttctactactaatt 36468 36481 2-10-2 836_1 TTctactactaaTT  837cttctactactaat 36469 36482 2-10-2 837_1 CTtctactactaAT  838acttctactactaa 36470 36483 2-10-2 838_1 ACttctactactAA  839aacttctactacta 36471 36484 2-10-2 839_1 AActtctactacTA  840caacttctactact 36472 36485 2-10-2 840_1 CAacttctactaCT  841tcaacttctactac 36473 36486 2-10-2 841_1 TCaacttctactAC  842ctcaacttctacta 36474 36487 2-10-2 842_1 CTcaacttctacTA  843tctcaacttctact 36475 36488 2-10-2 843_1 TCtcaacttctaCT  844ctctcaacttctac 36476 36489 2-10-2 844_1 CTctcaacttctAC  845tctctcaacttcta 36477 36490 2-10-2 845_1 TCtctcaacttcTA  846ttctctcaacttct 36478 36491 2-10-2 846_1 TTctctcaacttCT  847tttctctcaacttc 36479 36492 2-10-2 847_1 TTtctctcaactTC  848ttttctctcaactt 36480 36493 2-10-2 848_1 TTttctctcaacTT  849tttttctctcaact 36481 36494 2-10-2 849_1 TTtttctctcaaCT  850ctttttctctcaac 36482 36495 2-10-2 850_1 CTttttctctcaAC  851actttttctctcaa 36483 36496 2-10-2 851_1 ACtttttctctcAA  852tactttttctctca 36484 36497 2-10-2 852_1 TActttttctctCA  853ttactttttctctc 36485 36498 2-10-2 853_1 TTactttttctcTC  854gttactttttctct 36486 36499 2-10-2 854_1 GTtactttttctCT  855agttactttttctc 36487 36500 2-10-2 855_1 AGttac11111cTC  856cattcccattaaca 36788 36801 2-10-2 856_1 CAttcccattaaCA  857acattcccattaac 36789 36802 2-10-2 857_1 ACattcccattaAC  858tacattcccattaa 36790 36803 2-10-2 858_1 TAcattcccattAA  859ttacattcccatta 36791 36804 2-10-2 859_1 TTacattcccatTA  860tttacattcccatt 36792 36805 2-10-2 860_1 TTtacattcccaTT  861ttttacattcccat 36793 36806 2-10-2 861_1 TTttacattcccAT  862cttttacattccca 36794 36807 2-10-2 862_1 CTtttacattccCA  863acttttacattccc 36795 36808 2-10-2 863_1 ACttttacattcCC  864cacttttacattcc 36796 36809 2-10-2 864_1 CActtttacattCC  865acacttttacattc 36797 36810 2-10-2 865_1 ACacttttacatTC  866tacacttttacatt 36798 36811 2-10-2 866_1 TAcacttttacaTT  867gtacacttttacat 36799 36812 2-10-2 867_1 GTacacttttacAT  868tgtacacttttaca 36800 36813 2-10-2 868_1 TGtacacttttaCA  869tttatcaaaaaaat 36834 36847 2-10-2 869_1 TTtatcaaaaaaAT  870atttatcaaaaaaa 36835 36848 2-10-2 870_1 ATttatcaaaaaAA  871catttatcaaaaaa 36836 36849 2-10-2 871_1 CAtttatcaaaaAA  872acatttatcaaaaa 36837 36850 2-10-2 872_1 ACatttatcaaaAA  873tacatttatcaaaa 36838 36851 2-10-2 873_1 TAcatttatcaaAA  874atacatttatcaaa 36839 36852 2-10-2 874_1 ATacatttatcaAA  875tatacatttatcaa 36840 36853 2-10-2 875_1 TAtacatttatcAA  876acatcttccaattt 38848 38861 2-10-2 876_1 ACatcttccaatTT  877tacatcttccaatt 38849 38862 2-10-2 877_1 TAcatcttccaaTT  878ttacatcttccaat 38850 38863 2-10-2 878_1 TTacatcttccaAT  879tttacatcttccaa 38851 38864 2-10-2 879_1 TTtacatcttccAA  880atttacatcttcca 38852 38865 2-10-2 880_1 ATttacatcttcCA  881tatttacatcttcc 38853 38866 2-10-2 881_1 TAtttacatcttCC  882ttatttacatcttc 38854 38867 2-10-2 882_1 TTatttacatctTC  883cttatttacatctt 38855 38868 2-10-2 883_1 CTtatttacatcTT  884tcttatttacatct 38856 38869 2-10-2 884_1 TCttatttacatCT  885atcttatttacatc 38857 38870 2-10-2 885_1 ATcttatttacaTC  886aatcttatttacat 38858 38871 2-10-2 886_1 AAtcttatttacAT  887gaatcttatttaca 38859 38872 2-10-2 887_1 GAatcttatttaCA  888tgaatcttatttac 38860 38873 2-10-2 888_1 TGaatcttatttAC  889ttcccttcactcct 40071 40084 2-10-2 889_1 TTcccttcactcCT  890tttcccttcactcc 40072 40085 2-10-2 890_1 TTtcccttcactCC  891ttttcccttcactc 40073 40086 2-10-2 891_1 TTttcccttcacTC  892attttcccttcact 40074 40087 2-10-2 892_1 ATtttcccttcaCT  893aattttcccttcac 40075 40088 2-10-2 893_1 AAttttcccttcAC  894taattttcccttca 40076 40089 2-10-2 894_1 TAattttcccttCA  895ttaattttcccttc 40077 40090 2-10-2 895_1 TTaattttccctTC  896gttaattttccctt 40078 40091 2-10-2 896_1 GTtaattttcccTT  897tttatcatttcttt 40150 40163 2-10-2 897_1 TTtatcatttctTT  898ttttatcatttctt 40151 40164 2-10-2 898_1 TTttatcatttcTT  899cttttatcatttct 40152 40165 2-10-2 899_1 CTtttatcatttCT  900tcttttatcatttc 40153 40166 2-10-2 900_1 TCttttatcattTC  901ttcttttatcattt 40154 40167 2-10-2 901_1 TTcttttatcatTT  902cttcttttatcatt 40155 40168 2-10-2 902_1 CTtcttttatcaTT  903acttcttttatcat 40156 40169 2-10-2 903_1 ACttcttttatcAT  904tacttcttttatca 40157 40170 2-10-2 904_1 TActtcttttatCA  905ttacttcttttatc 40158 40171 2-10-2 905_1 TTacttcttttaTC  906attacttcttttat 40159 40172 2-10-2 906_1 ATtacttcttttAT  907aattacttctttta 40160 40173 2-10-2 907_1 AAttacttctttTA  908aaattacttctttt 40161 40174 2-10-2 908_1 AAattacttcttTT  909aaaattacttcttt 40162 40175 2-10-2 909_1 AAaattacttctTT  910caaaattacttctt 40163 40176 2-10-2 910_1 CAaaattacttcTT  911ccaaaattacttct 40164 40177 2-10-2 911_1 CCaaaattacttCT  912tccaaaattacttc 40165 40178 2-10-2 912_1 TCcaaaattactTC  913ttccaaaattactt 40166 40179 2-10-2 913_1 TTccaaaattacTT  914gttccaaaattact 40167 40180 2-10-2 914_1 GTtccaaaattaCT  915tgttccaaaattac 40168 40181 2-10-2 915_1 TGttccaaaattAC  916atgttccaaaatta 40169 40182 2-10-2 916_1 ATgttccaaaatTA  917ttactctttttatt 40201 40214 2-10-2 917_1 TTactctttttaTT  918tttactctttttat 40202 40215 2-10-2 918_1 TTtactctttttAT  919ttttactcttttta 40203 40216 2-10-2 919_1 TTttactcttttTA  920attttactcttttt 40204 40217 2-10-2 920_1 ATtttactctttTT  921tattttactctttt 40205 40218 2-10-2 921_1 TAttttactcttTT  922atattttactcttt 40206 40219 2-10-2 922_1 ATattttactctTT  923catattttactctt 40207 40220 2-10-2 923_1 CAtattttactcTT  924ccatattttactct 40208 40221 2-10-2 924_1 CCatattttactCT  925cccatattttactc 40209 40222 2-10-2 925_1 CCcatattttacTC  926acccatattttact 40210 40223 2-10-2 926_1 ACccatattttaCT  927tacccatattttac 40211 40224 2-10-2 927_1 TAcccatattttAC  928ttacccatatttta 40212 40225 2-10-2 928_1 TTacccatatttTA  929tttacccatatttt 40213 40226 2-10-2 929_1 TTtacccatattTT  930gtttacccatattt 40214 40227 2-10-2 930_1 GTttacccatatTT  931tgtttacccatatt 40215 40228 2-10-2 931_1 TGtttacccataTT  932gttacctcccttta 40368 40381 2-10-2 932_1 GTtacctcccttTA  933ggttacctcccttt 40369 40382 2-10-2 933_1 GGttacctccctTT  934aggttacctccctt 40370 40383 2-10-2 934_1 AGgttacctcccTT  935caaactaaaaccta 41659 41672 2-10-2 935_1 CAaactaaaaccTA  936tcaaactaaaacct 41660 41673 2-10-2 936_1 TCaaactaaaacCT  937atcaaactaaaacc 41661 41674 2-10-2 937_1 ATcaaactaaaaCC  938gatcaaactaaaac 41662 41675 2-10-2 938_1 GAtcaaactaaaAC  939agatcaaactaaaa 41663 41676 2-10-2 939_1 AGatcaaactaaAA  940aagatcaaactaaa 41664 41677 2-10-2 940_1 AAgatcaaactaAA  941ccaatttcacccaa 41699 41712 2-10-2 941_1 CCaatttcacccAA  942cccaatttcaccca 41700 41713 2-10-2 942_1 CCcaatttcaccCA  943gcccaatttcaccc 41701 41714 2-10-2 943_1 GCccaatttcacCC  944tgcccaatttcacc 41702 41715 2-10-2 944_1 TGcccaatttcaCC  945ttgcccaatttcac 41703 41716 2-10-2 945_1 TTgcccaatttcAC  946caactttctatttt 41777 41790 2-10-2 946_1 CAactttctattTT  947ccaactttctattt 41778 41791 2-10-2 947_1 CCaactttctatTT  948cccaactttctatt 41779 41792 2-10-2 948_1 CCcaactttctaTT  949acccaactttctat 41780 41793 2-10-2 949_1 ACccaactttctAT  950aacccaactttcta 41781 41794 2-10-2 950_1 AAcccaactttcTA  951aaacccaactttct 41782 41795 2-10-2 951_1 AAacccaactttCT  952aaaacccaactttc 41783 41796 2-10-2 952_1 AAaacccaacttTC  953aaaaacccaacttt 41784 41797 2-10-2 953_1 AAaaacccaactTT  954caaaaacccaactt 41785 41798 2-10-2 954_1 CAaaaacccaacTT  955acaaaaacccaact 41786 41799 2-10-2 955_1 ACaaaaacccaaCT  956ctttaaaatttcca 42170 42183 2-10-2 956_1 CTttaaaatttcCA  957tctttaaaatttcc 42171 42184 2-10-2 957_1 TCtttaaaatttCC  958ttctttaaaatttc 42172 42185 2-10-2 958_1 TTctttaaaattTC  959tttctttaaaattt 42173 42186 2-10-2 959_1 TTtctttaaaatTT  960atttctttaaaatt 42174 42187 2-10-2 960_1 ATttctttaaaaTT  961catttctttaaaat 42175 42188 2-10-2 961_1 CAtttctttaaaAT  962acatttctttaaaa 42176 42189 2-10-2 962_1 ACatttctttaaAA  963cacatttctttaaa 42177 42190 2-10-2 963_1 CAcatttctttaAA  964ccacatttctttaa 42178 42191 2-10-2 964_1 CCacatttctttAA  965accacatttcttta 42179 42192 2-10-2 965_1 ACcacatttcttTA  966aaccacatttcttt 42180 42193 2-10-2 966_1 AAccacatttctTT  967aaaccacatttctt 42181 42194 2-10-2 967_1 AAaccacatttcTT  968aaaaccacatttct 42182 42195 2-10-2 968_1 AAaaccacatttCT  969caaaaccacatttc 42183 42196 2-10-2 969_1 CAaaaccacattTC  970ttcttctcttttca 43831 43844 2-10-2 970_1 TTcttctcttttCA  971tttcttctcttttc 43832 43845 2-10-2 971_1 TTtcttctctttTC  972ttttcttctctttt 43833 43846 2-10-2 972_1 TTttcttctcttTT  973tttttcttctcttt 43834 43847 2-10-2 973_1 TTtttcttctctTT  974ttttttcttctctt 43835 43848 2-10-2 974_1 TTttttcttctcTT  975attttttcttctct 43836 43849 2-10-2 975_1 ATtttttcttctCT  976tattttttcttctc 43837 43850 2-10-2 976_1 TAttttttcttcTC  977aacttaatattaaa 45488 45501 2-10-2 977_1 AActtaatattaAA  978caacttaatattaa 45489 45502 2-10-2 978_1 CAacttaatattAA  979tcaacttaatatta 45490 45503 2-10-2 979_1 TCaacttaatatTA  980ttcaacttaatatt 45491 45504 2-10-2 980_1 TTcaacttaataTT  981attcaacttaatat 45492 45505 2-10-2 981_1 ATtcaacttaatAT  982tattcaacttaata 45493 45506 2-10-2 982_1 TAttcaacttaaTA  983ttattcaacttaat 45494 45507 2-10-2 983_1 TTattcaacttaAT  984tttattcaacttaa 45495 45508 2-10-2 984_1 TTtattcaacttAA  985caaattaaaaaaca 47397 47410 2-10-2 985_1 CAaattaaaaaaCA  986tcaaattaaaaaac 47398 47411 2-10-2 986_1 TCaaattaaaaaAC  987ttcaaattaaaaaa 47399 47412 2-10-2 987_1 TTcaaattaaaaAA  988cttcaaattaaaaa 47400 47413 2-10-2 988_1 CTtcaaattaaaAA  989tcttcaaattaaaa 47401 47414 2-10-2 989_1 TCttcaaattaaAA  990ttcttcaaattaaa 47402 47415 2-10-2 990_1 TTcttcaaattaAA  991tttcttcaaattaa 47403 47416 2-10-2 991_1 TTtcttcaaattAA  992aacacaaattcaaa 48077 48090 2-10-2 992_1 AAcacaaattcaAA  993aaacacaaattcaa 48078 48091 2-10-2 993_1 AAacacaaattcAA  994taaacacaaattca 48079 48092 2-10-2 994_1 TAaacacaaattCA  995ataaacacaaattc 48080 48093 2-10-2 995_1 ATaaacacaaatTC  996aataaacacaaatt 48081 48094 2-10-2 996_1 AAtaaacacaaaTT  997caataaacacaaat 48082 48095 2-10-2 997_1 CAataaacacaaAT  998acaataaacacaaa 48083 48096 2-10-2 998_1 ACaataaacacaAA  999aacaataaacacaa 48084 48097 2-10-2 999_1 AAcaataaacacAA 1000taacaataaacaca 48085 48098 2-10-2 1000_1 TAacaataaacaCA 1001ttaacaataaacac 48086 48099 2-10-2 1001_1 TTaacaataaacAC 1002attaacaataaaca 48087 48100 2-10-2 1002_1 ATtaacaataaaCA 1003aattaacaataaac 48088 48101 2-10-2 1003_1 AAttaacaataaAC 1004gaattaacaataaa 48089 48102 2-10-2 1004_1 GAattaacaataAA 1005tgaattaacaataa 48090 48103 2-10-2 1005_1 TGaattaacaatAA 1006atattcctcaatca 48905 48918 2-10-2 1006_1 ATattcctcaatCA 1007tatattcctcaatc 48906 48919 2-10-2 1007_1 TAtattcctcaaTC 1008atatattcctcaat 48907 48920 2-10-2 1008_1 ATatattcctcaAT 1009aatatattcctcaa 48908 48921 2-10-2 1009_1 AAtatattcctcAA 1010caatatattcctca 48909 48922 2-10-2 1010_1 CAatatattcctCA 1011acaatatattcctc 48910 48923 2-10-2 1011_1 ACaatatattccTC 1012gacaatatattcct 48911 48924 2-10-2 1012_1 GAcaatatattcCT 1013caatcctaattaaa 48960 48973 2-10-2 1013_1 CAatcctaattaAA 1014ccaatcctaattaa 48961 48974 2-10-2 1014_1 CCaatcctaattAA 1015cccaatcctaatta 48962 48975 2-10-2 1015_1 CCcaatcctaatTA 1016gcccaatcctaatt 48963 48976 2-10-2 1016_1 GCccaatcctaaTT 1017tgcccaatcctaat 48964 48977 2-10-2 1017_1 TGcccaatcctaAT 1018accctacaaatact 50093 50106 2-10-2 1018_1 ACcctacaaataCT 1019aaccctacaaatac 50094 50107 2-10-2 1019_1 AAccctacaaatAC 1020aaaccctacaaata 50095 50108 2-10-2 1020_1 AAaccctacaaaTA 1021aaaaccctacaaat 50096 50109 2-10-2 1021_1 AAaaccctacaaAT 1022aaaaaccctacaaa 50097 50110 2-10-2 1022_1 AAaaaccctacaAA 1023aaaaaaccctacaa 50098 50111 2-10-2 1023_1 AAaaaaccctacAA 1024aaaaaaaccctaca 50099 50112 2-10-2 1024_1 AAaaaaaccctaCA 1025tatacactattaat 51008 51021 2-10-2 1025_1 TAtacactattaAT 1026ttatacactattaa 51009 51022 2-10-2 1026_1 TTatacactattAA 1027attatacactatta 51010 51023 2-10-2 1027_1 ATtatacactatTA 1028aattatacactatt 51011 51024 2-10-2 1028_1 AAttatacactaTT 1029gaattatacactat 51012 51025 2-10-2 1029_1 GAattatacactAT 1030gtaacaattataca 51866 51879 2-10-2 1030_1 GTaacaattataCA 1031tgtaacaattatac 51867 51880 2-10-2 1031_1 TGtaacaattatAC 1032ctgtaacaattata 51868 51881 2-10-2 1032_1 CTgtaacaattaTA 1033cctgtaacaattat 51869 51882 2-10-2 1033_1 CCtgtaacaattAT 1034tcctgtaacaatta 51870 51883 2-10-2 1034_1 TCctgtaacaatTA 1035ataaaaaccacctt 53263 53276 2-10-2 1035_1 ATaaaaaccaccTT 1036aataaaaaccacct 53264 53277 2-10-2 1036_1 AAtaaaaaccacCT 1037gaataaaaaccacc 53265 53278 2-10-2 1037_1 GAataaaaaccaCC 1038agaataaaaaccac 53266 53279 2-10-2 1038_1 AGaataaaaaccAC 1039cagaataaaaacca 53267 53280 2-10-2 1039_1 CAgaataaaaacCA 1040ccagaataaaaacc 53268 53281 2-10-2 1040_1 CCagaataaaaaCC 1041cccagaataaaaac 53269 53282 2-10-2 1041_1 CCcagaataaaaAC 1042acccagaataaaaa 53270 53283 2-10-2 1042_1 ACccagaataaaAA 1043tttcttactcccct 53699 53712 2-10-2 1043_1 TTtcttactcccCT 1044ctttcttactcccc 53700 53713 2-10-2 1044_1 CTttcttactccCC 1045actttcttactccc 53701 53714 2-10-2 1045_1 ACtttcttactcCC 1046cactttcttactcc 53702 53715 2-10-2 1046_1 CActttcttactCC 1047ccactttcttactc 53703 53716 2-10-2 1047_1 CCactttcttacTC 1048cctttaccactttt 53948 53961 2-10-2 1048_1 CCtttaccacttTT 1049ccctttaccacttt 53949 53962 2-10-2 1049_1 CCctttaccactTT 1050tccctttaccactt 53950 53963 2-10-2 1050_1 TCcctttaccacTT 1051atccctttaccact 53951 53964 2-10-2 1051_1 ATccctttaccaCT 1052catccctttaccac 53952 53965 2-10-2 1052_1 CAtccctttaccAC 1053ctacatctaacccc 54550 54563 2-10-2 1053_1 CTacatctaaccCC 1054tctacatctaaccc 54551 54564 2-10-2 1054_1 TCtacatctaacCC 1055gtctacatctaacc 54552 54565 2-10-2 1055_1 GTctacatctaaCC 1056agtctacatctaac 54553 54566 2-10-2 1056_1 AGtctacatctaAC 1057cagtctacatctaa 54554 54567 2-10-2 1057_1 CAgtctacatctAA 1058tcagtctacatcta 54555 54568 2-10-2 1058_1 TCagtctacatcTA 1059ttcagtctacatct 54556 54569 2-10-2 1059_1 TTcagtctacatCT 1060taaccacacctcct 54573 54586 2-10-2 1060_1 TAaccacacctcCT 1061ttaaccacacctcc 54574 54587 2-10-2 1061_1 TTaaccacacctCC 1062tttaaccacacctc 54575 54588 2-10-2 1062_1 TTtaaccacaccTC 1063ttttaaccacacct 54576 54589 2-10-2 1063_1 TTttaaccacacCT 1064gttttaaccacacc 54577 54590 2-10-2 1064_1 GTtttaaccacaCC 1065agttttaaccacac 54578 54591 2-10-2 1065_1 AGttttaaccacAC 1066caacaaaacatcaa 55228 55241 2-10-2 1066_1 CAacaaaacatcAA 1067tcaacaaaacatca 55229 55242 2-10-2 1067_1 TCaacaaaacatCA 1068ttcaacaaaacatc 55230 55243 2-10-2 1068_1 TTcaacaaaacaTC 1069tttcaacaaaacat 55231 55244 2-10-2 1069_1 TTtcaacaaaacAT 1070ttttcaacaaaaca 55232 55245 2-10-2 1070_1 TTttcaacaaaaCA 1071gttttcaacaaaac 55233 55246 2-10-2 1071_1 GTtttcaacaaaAC 1072tgttttcaacaaaa 55234 55247 2-10-2 1072_1 TGttttcaacaaAA 1073ttctaaaacttacc 55269 55282 2-10-2 1073_1 TTctaaaacttaCC 1074tttctaaaacttac 55270 55283 2-10-2 1074_1 TTtctaaaacttAC 1075ctttctaaaactta 55271 55284 2-10-2 1075_1 CTttctaaaactTA 1076tctttctaaaactt 55272 55285 2-10-2 1076_1 TCtttctaaaacTT 1077atctttctaaaact 55273 55286 2-10-2 1077_1 ATctttctaaaaCT 1078aatctttctaaaac 55274 55287 2-10-2 1078_1 AAtctttctaaaAC 1079gaatctttctaaaa 55275 55288 2-10-2 1079_1 GAatctttctaaAA 1080agaatctttctaaa 55276 55289 2-10-2 1080_1 AGaatctttctaAA 1081cagaatctttctaa 55277 55290 2-10-2 1081_1 CAgaatctttctAA 1082cctttatttccctt 55494 55507 2-10-2 1082_1 CCtttatttcccTT 1083ccctttatttccct 55495 55508 2-10-2 1083_1 CCctttatttccCT 1084tccctttatttccc 55496 55509 2-10-2 1084_1 TCcctttatttcCC 1085ttccctttatttcc 55497 55510 2-10-2 1085_1 TTccctttatttCC 1086tttccctttatttc 55498 55511 2-10-2 1086_1 TTtccctttattTC 1087atttccctttattt 55499 55512 2-10-2 1087_1 ATttccctttatTT 1088tatttccctttatt 55500 55513 2-10-2 1088_1 TAtttccctttaTT 1089gtatttccctttat 55501 55514 2-10-2 1089_1 GTatttccctttAT

Example 2: In vitro reduction of ATXN3 in SK-N-AS human cell line usingfurther LNA gapmer oligonucleotides targeting ATNX3 Materials andMethods:

LNA modified oligonucleotides targeting human ATXN3 were tested fortheir ability to reduce ATXN3 mRNA expression in human SK-N-ASneuroblastoma cells acquired from ECACC Cat: 94092302. The cells werecultured according to the vendor guidelines in Dulbecco's ModifiedEagle's Medium, supplemented with 0.1 mM Non-Essential Amino Acids(NEAA) and fetal bovine serum to a final concentration of 10%. Cellswere cultured at 37° C., 5% CO2 and 95% humidity in an activeevaporation incubator (Thermo C10). Cells were seeded at a density of9000 cells per well (96-well plate) in 190 ul of SK-N-AS cell culturemedium. The cells were hereafter added 10 μl of oligo suspension or PBS(controls) to a final concentration of 5 μM from pre-made 96-welldilution plates. The cell culture plates were incubated for 72 hours inthe incubator.

After incubation, cells were harvested by removal of media followed bycell lysis and RNA purification using QIAGEN RNeasy 96 Kit (cat 74181),following manufacturers protocol. RNA was diluted 2 fold in water priorto the one-step qPCR reaction. For one-step qPCR reaction qPCR-mix(qScriptTM XLT One-Step RT-qPCR ToughMix® Low ROX from QuantaBio, cat.no95134-500) and QPCR was run as duplex QPCR using assays from IntegratedDNA technologies for ATXN3 (Hs.PT.58.39355049) and TBP(Hs.PT.58v.39858774)

Hs.PT.58.39355049 - Primer Sequences Probe: (SEQ ID NO: 1130)5′-/56-FAM/AAAGGCCAG/ZEN/CCACCAGTTCAGG/3IABkFQ/-3′ Primer 1:(SEQ ID NO: 1129) 5′-CTATCAGGACAGAGTTCACATCC-3′ Primer 2:(SEQ ID NO: 1128) 5′-GTTTCTAAAGACATGGTCACAGC-3′Hs.PT.58v.39858774 - Primer Sequences Probe: (SEQ ID NO: 1131)5′-/5HEX/TGA TCT TTG/ZEN/CAG TGA CCC AGC ATC A/ 3IABkFQ/-3′ Primer 1:(SEQ ID NO: 1132) 5′-GCT GTT TAA CTT CGC TTC CG-3′ Primer 2:(SEQ ID NO: 1133) 5′-CAG CAA CTT CCT CAA TTC CTT G-3′

The reactions were then mixed in a qPCR plate (MICROAMP®optical 384well, 4309849). After sealing, the plate was given a quick spin, 1000 gfor 1 minute at RT, and transferred to a Viia™ 7 system (AppliedBiosystems, Thermo), and the following PCR conditions used: 50° C. for15 minutes; 95° C. for 3 minutes; 40 cycles of: 95° C. for 5 secfollowed by a temperature decrease of 1.6° C./sec followed by 60° C. for45 sec. The data was analyzed using the QuantStudio™ Real time PCRSoftware and quantity calculated by the delta delta Ct method(Quantity=2{circumflex over ( )}(−Ct)*1000000000). Quantity isnormalized to the calculated quantity for the housekeeping gene assay(TBP) run in the same well. Relative TargetQuantity=QUANTITY_target/QUANTITY_housekeeping (RNA knockdown) wascalculated for each well by division with the mean of all PBS-treatedwells on the same plate. Normalised Target Quantity=(Relative TargetQuantity/[mean] Relative Target Quantity]_pbs_wells)*100.

Compounds targeting selected target sequence regions of SEQ ID NO:1 wereevaluated in the above assay.

Results:

The target knock-down data is presented in the following Compound andData Table:

In the Compound table, motif sequences represent the contiguous sequenceof nucleobases present in the oligonucleotide.

Oligonucleotide compound represent specific designs of a motif sequence.Capital letters represent beta-D-oxy LNA nucleosides, lowercase lettersrepresent DNA nucleosides, all LNA C are 5-methyl cytosine, allinternucleoside linkages are phosphorothioate internucleoside linkages.

TABLE 4 Compound and Data Table % of ATXN3 OligonucleotideOligonucleotide mRNA SEQID CMPID Base Sequence compound remaining 10991099_1 CCAAAAGAAACCAAACCC CCAAaagaaaccaaacCC 90.6 1100 1100_1CCCCATTCAAATATTTATT CCccattcaaatatttATT 90.5 1101 1101_1AATCATTTACCCCCAAC AAtcatttaccccCAAC 92 1102 1102_1 TATCTCAAACTATCCCCATAtctcaaactatcccCA 93 1103 1103_1 TCTATTCCTTAACCCAAC TCTattccttaacccAAC76.6 1104 1104_1 TCCCCTAAATAATTTAATCA TCccctaaataatttaATCA 79.3 11051105_1 AAACCACTCCATTCCAA AaaccactccattCCAA 57.7 1106 1106_1TCTAAACCCCAAACTTTCA TCtaaaccccaaactttCA 74.3 1107 1107_1TTCTAAACCCCAAACTTTC TTCtaaaccccaaacttTC 61.8 1108 1108_1AGTTCTAAACCCCAAACT AGttctaaaccccaaACT 73.7 1109 1109_1TGAAACCATTACTACAACC TGaaaccattactacAACC 24.9 1110 1110_1ACATCATTTATCACTACCAC ACAtcatttatcactaccAC 71.9 1111 1111_1AACATTAAACCCTCCCA AacattaaaccctcCCA 80.2 1112 1112_1 TCAGATCCTAAAATCACTTCAgatcctaaaatcACT 79.5 1113 1113_1 CTATACCTAAAACAATCTACTAtacctaaaacaatCTA 99.1 1114 1114_1 TGATTCTTATACTTACTATGAttcttatacttaCTA 72.1 1115 1115_1 TAAAAATATAACTACTCCTATAaaaatataactactCCTA 93.7 1116 1116_1 TCTTCATTATACCATCAAATTCTtcattataccatcaAAT 51.5 1117 1117_1 GTTTCATATTTTTAATCCGTTtcatatttttaaTCC 37.7 1118 1118_1 TAATATCCTCATTACCCATTTAatatcctcattacccaTT 84 1119 1119_1 CAAATATTCACAAATCCTACAaatattcacaaatCCTA 73.3 1120 1120_1 CATCACAAAATAACCTATACCATcacaaaataacctaTCA 79.9 1121 1121_1 CTCTCAACTTCTACTACTAACTCtcaacttctactactAA 59.6 1122 1122_1 AATCTTATTTACATCTTCCAATcttatttacatctTCC 20.7 1123 1123_1 CCAAAATTACTTCTTTTATCCCAaaattacttcttttATC 56.5 1124 1124_1 AACCCAACTTTCTATTTTAACCcaactttctattTT 52.7 1125 1125_1 ACAATATATTCCTCAATCAACAatatattcctcaaTCA 86.8 1126 1126_1 CCTGTAACAATTATACA CCTgtaacaattatACA92.3 1127 1127_1 CATCCCTTTACCACTTT CAtccctttaccactTT 94.5

In the oligonucleotide compound column, capital letters representbeta-D-oxy LNA nucleosides, LNA cytosines are 5-methyl cytosine, lowercase letters are DNA nucleosides, and all internucleoside linkages arephosphorothioate.

As can be seen, most of the above compounds targeting the listed targetsequence regions are capable of inhibiting the expression of the humanataxin 3 transcript and that compounds targeting the target sequenceregion complementary to SEQ ID NOS:1122 and 1109 are particularlyeffective in inhibiting the human ataxin 3 transcript. Other effectivetarget sites for ATXN3 can be determined from the above table.

Example 3 Materials and Methods:

The screening assay described in Example 2 was performed using a seriesof further oligonucleotide targeting human ATXN3 pre-mRNA using theqpCR: (ATXN3 exon 8-9(1) PrimeTime® XL qPCR Assay (IDT).

qPCR probe and primers set 2: Probe: (SEQ ID NO: 1134)5′-/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCT AAGT/ 31ABkFQ/-3′ Primer 1:(SEQ ID NO: 1135) 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′ Primer 2:(SEQ ID NO: 1136) 5′-CATGGAAGATGAGGAAGCAGAT-3′

Results:

The results are shown in the following table:

TABLE 5 % of ATXN3 Oligonucleotide Oligonucleotide mRNA SEQID CMPIDBase Sequence compound remaining 1137 1137_1 CCTACTTCACTTCCTAACctacttcacttcCTAA 68.9 1138 1138_1 TTTCCTACTTCACTTCCTATttcctacttcacttccTA 95.1 1139 1139_1 TTCCTACTTCACTTCCTATtcctacttcacttcCTA 85 1140 1140_1 TTTCCTACTTCACTTCCT TTtcctacttcacttcCT88.1 1141 1141_1 TTTCCTACTTCACTTCC TttcctacttcactTCC 83.1 1142 1142_1GTTTCCTACTTCACTTC GTTtcctacttcactTC 60.2 1143 1143_1 ACCAAACCCAAACATCCCAccaaacccaaacatcCC 88 1144 1144_1 AGAAACCAAACCCAAACATCAgaaaccaaacccaaaCATC 91.3 1145 1145_1 AGAAACCAAACCCAAACATAGaaaccaaacccaaACAT 93.5 1146 1146_1 CTCCTAATACCTAAAAACAAACTCCtaatacctaaaaacaAA 100 1147 1147_1 CTCCTAATACCTAAAAACACTCCtaatacctaaaaaCA 94.2 1148 1148_1 ACTCCTAATACCTAAAAACAACTCctaatacctaaaaaCA 81 1149 1149_1 CACTCCTAATACCTAAAAACACACtcctaatacctaaaaACA 90.4 1150 1150_1 CCACTCCTAATACCTAAAAACCACtcctaatacctaaaAA 63 1151 1151_1 TCCACTCCTAATACCTAAAAATCCactcctaatacctaaaAA 54 1152 1152_1 CCACTCCTAATACCTAAAACCACtcctaatacctaaAA 73.7 1153 1153_1 TCCACTCCTAATACCTAAAATCCactcctaatacctaAAA 59 1154 1154_1 CCACTCCTAATACCTAAACCACtcctaatacctaAA 65.2 1155 1155_1 GTCCACTCCTAATACCTAAAGtccactcctaataccTAAA 86.8 1156 1156_1 CCACTCCTAATACCTAACCactcctaatacCTAA 52.3 1157 1157_1 TCCACTCCTAATACCTAA TCcactcctaatacCTAA64.3 1157 1157_2 TCCACTCCTAATACCTAA TCCActcctaatacctAA 66 1158 1158_1GTCCACTCCTAATACCTAA GtccactcctaataccTAA 85.5 1159 1159_1AGTCCACTCCTAATACCTA AgtccactcctaataccTA 87.4 1160 1160_1TCCACTCCTAATACCTA TCcactcctaatacCTA 70.1 1161 1161_1 AGTCCACTCCTAATACCTAgtccactcctaatacCT 84.2 1162 1162_1 GTCCACTCCTAATACC GTCcactcctaataCC57.8 1163 1163_1 AGTCCACTCCTAATACC AGtccactcctaataCC 77.1 1164 1164_1CAGTCCACTCCTAATACC CagtccactcctaatACC 86.7 1162 1162_2 GTCCACTCCTAATACCGTCcactcctaatACC 67.8 1165 1165_1 CCAGTCCACTCCTAATAC CcagtccactcctaaTAC85.4 1166 1166_1 CAGTCCACTCCTAATAC CAgtccactcctaaTAC 60.7 1167 1167_1AGTCCACTCCTAATAC AGTCcactcctaatAC 78.9 1168 1168_1 CAGTCCACTCCTAATACAGtccactcctaaTA 44.5 1169 1169_1 CCAGTCCACTCCTAATA CCagtccactcctaaTA33.8 1170 1170_1 GCAACTCTTTCCAAACA GCAActctttccaaaCA 36 1171 1171_1AGCAACTCTTTCCAAACA AGCaactctttccaaaCA 35.3 1172 1172_1CAGCAACTCTTTCCAAACA CAgcaactctttccaaACA 58.3 1173 1173_1CCAGCAACTCTTTCCAAA CcagcaactctttcCAAA 69.7 1174 1174_1 CCAGCAACTCTTTCCAACCagcaactctttcCAA 42.1 1175 1175_1 ACCAGCAACTCTTTCCAA ACcagcaactctttcCAA65 1176 1176_1 TTACCAGCAACTCTTTC TTACcagcaactcttTC 53 1177 1177_1TGCTCCTCCTATTAAATAA TGCtcctcctattaaatAA 76.3 1178 1178_1GCTCCTCCTATTAAATAA GCtcctcctattaaATAA 61.8 1179 1179_1 GCTCCTCCTATTAAATAGCtcctcctattaaATA 60.2 1180 1180_1 TGCTCCTCCTATTAAATA TGctcctcctattaaATA70.2 1181 1181_1 TGCTCCTCCTATTAAAT TGCtcctcctattaaAT 80.2 1182 1182_1TTGCTCCTCCTATTAAAT TTGCtcctcctattaaAT 79 1183 1183_1ATTTAATAAAACAAAAACCCT ATttaataaaacaaaaaCCCT 97.2 1184 1184_1GCCCAAAAAACTAAATT GCCCaaaaaactaaaTT 95.5 1185 1185_1 GTTTTTACATTCTAACTTGTTtttacattctaaCTT 54.1 1186 1186_1 TGTTTTTACATTCTAACTTGTTtttacattctaaCT 63.8 1187 1187_1 CTGTTTTTACATTCTAACCTGTttttacattctaAC 62.5 1188 1188_1 CCCCATTCAAATATTTATCCCcattcaaatattTAT 64.9 1189 1189_1 GCCCCATTCAAATATTTATGCcccattcaaatattTAT 86.2 1188 1188_2 CCCCATTCAAATATTTATCCCCattcaaatatttAT 96.2 1190 1190_1 GCCCCATTCAAATATTTAGCcccattcaaatatTTA 82.2 1191 1191_1 CCATTCAAATATATACATTTTCCATtcaaatatatacattTT 72 1191 1191_2 CCATTCAAATATATACATTTTCCATtcaaataTatacattTT 37.7 1192 1192_1 TCCATTCAAATATATACATTTTCCAttcaaatatatacatTT 56.8 1193 1193_1 ATCCATTCAAATATATACATTATCCattcaaaTatatacaTT 48 1194 1194_1 TCCATTCAAATATATACATTTCCAttcaaatatatacaTT 53.7 1193 1193_2 ATCCATTCAAATATATACATTATCCattcaaatatatacaTT 54.7 1195 1195_1 TATCCATTCAAATATATACATTATccattcaaatatataCAT 80.1 1196 1196_1 TCCATTCAAATATATACATTCCattcaaatatataCAT 43.1 1197 1197_1 ATCCATTCAAATATATACAATCCattcaaatatataCA 53.9 1198 1198_1 TTATCCATTCAAATATATACATTatccattcaaatataTACA 69.4 1199 1199_1 TCCATTCAAATATATACATCCAttcaaatatataCA 54.7 1200 1200_1 TATCCATTCAAATATATACATATCcattcaaatatataCA 53.3 1201 1201_1 CTTTATCCATTCAAATATATACTttatccattcaaataTATA 85.5 1202 1202_1 TCTTTATCCATTCAAATATATTCTttatccattcaaataTAT 62.6 1203 1203_1 CTCTTTATCCATTCAAATATACTCtttatccattcaaatATA 38.4 1204 1204_1 TCTTTATCCATTCAAATATATCtttatccattcaaaTATA 70.9 1203 1203_2 CTCTTTATCCATTCAAATATACTCTttatccattcaaataTA 33.6 1205 1205_1 CTTTATCCATTCAAATATACTttatccattcaaaTATA 78.4 1206 1206_1 TCTCTTTATCCATTCAAATATTCtctttatccattcaaaTAT 82 1207 1207_1 CTCTTTATCCATTCAAATATCTCtttatccattcaaaTAT 39.8 1208 1208_1 TCTTTATCCATTCAAATATTCTttatccattcaaaTAT 63.1 1209 1209_1 TCTCTTTATCCATTCAAATATCtctttatccattcaAATA 65.2 1210 1210_1 CTCTTTATCCATTCAAATACTCTttatccattcaaaTA 32.2 1211 1211_1 TCTCTTTATCCATTCAAATTCTCtttatccattcaaAT 42 1212 1212_1 TCTCTTTATCCATTCAAA TCTCtttatccattcaAA42.5 1213 1213_1 AGCACCATATATATCTCA AgcaccatatatatCTCA 16 1214 1214_1GCACCATATATATCTCA GCaccatatatatcTCA 16 1215 1215_1 CAGCACCATATATATCTCACagcaccatatatatCTCA 19.2 1215 1215_2 CAGCACCATATATATCTCACAgcaccatatatatcTCA 24.1 1216 1216_1 AGCACCATATATATCTC AGCaccatatatatcTC19.9 1217 1217_1 GCACCATATATATCTC GCACcatatatatcTC 82.7 1218 1218_1CAGCACCATATATATCTC CAgcaccatatatatCTC 21.1 1219 1219_1 CAGCACCATATATATCTCAGcaccatatataTCT 28.9 1220 1220_1 ACAGCACCATATATATCT ACAGcaccatatatatCT21.9 1221 1221_1 ACAGCACCATATATATC ACAGcaccatatataTC 25.4 1222 1222_1CTATGTTATTATCCCCA CTAtgttattatcccCA 56.1 1223 1223_1 TCTATGTTATTATCCCCTctatgttattatcCCC 47.7 1224 1224_1 CTCTACACTCTAACTCT CtctacactctaaCTCT79.3 1225 1225_1 TCTCTACACTCTAACTCT TctctacactctaaCTCT 79.6 1226 1226_1TTCTCTACACTCTAACTCT TTCtctacactctaactCT 86.9 1227 1227_1CTTCTCTACACTCTAACTCT CTtctctacactctaactCT 97 1227 1227_2CTTCTCTACACTCTAACTCT CttctctacactctaacTCT 84.5 1228 1228_1TTCTCTACACTCTAACTC TTCtctacactctaacTC 81.4 1229 1229_1CTTCTCTACACTCTAACTC CttctctacactctaaCTC 89.1 1230 1230_1TCTCTACACTCTAACTC TCtctacactctaaCTC 87.3 1231 1231_1CCTTCTCTACACTCTAACTC CcttctctacactctaacTC 98.3 1232 1232_1TTCTCTACACTCTAACT TTCTctacactctaaCT 80.1 1233 1233_1 CTTCTCTACACTCTAACTCTTctctacactctaaCT 73.6 1234 1234_1 CCTTCTCTACACTCTAACTCcttctctacactctAACT 77.7 1235 1235_1 CCTTCTCTACACTCTAACCCTtctctacactctaAC 82.4 1236 1236_1 CTTCTCTACACTCTAAC CTtctctacactcTAAC90.6 1237 1237_1 AGCCTTCTCTACACTCTAA AgccttctctacactcTAA 80 1238 1238_1CCTTCTCTACACTCTAA CCttctctacactcTAA 72.2 1239 1239_1 GCCTTCTCTACACTCTAAGCcttctctacactctAA 62.9 1240 1240_1 AGCCTTCTCTACACTCTAAgccttctctacactcTA 85.2 1241 1241_1 TACTAACTACAACACAAATCATACtaactacaacacaaaTCA 91.3 1241 1241_2 TACTAACTACAACACAAATCATACtaactacAacacaaaTCA 81.1 1242 1242_1 CTACTAACTACAACACAAATCCTACtaactacaacacaaaTC 108 1243 1243_1 CACTACTAACTACAACACAAACACTactaactacaacacaAA 74 1244 1244_1 CACTACTAACTACAACACAACACtactaactacaacaCAA 87.4 1245 1245_1 ACACTACTAACTACAACACAAACActactaactacaacaCAA 84.1 1246 1246_1 CACTACTAACTACAACACACACTactaactacaacaCA 83.5 1247 1247_1 ACACTACTAACTACAACACAACACtactaactacaacaCA 81.3 1248 1248_1 GACACTACTAACTACAACACGACactactaactacaaCAC 51.6 1249 1249_1 GACACTACTAACTACAACAGACActactaactacaaCA 51 1250 1250_1 AGACACTACTAACTACAA AGAcactactaactaCAA57.2 1251 1251_1 AGACACTACTAACTACA AGACactactaactaCA 34.7 1252 1252_1ATCATTTACCCCCAACCT AtcatttacccccaacCT 96 1253 1253_1 ATCATTTACCCCCAACCAtcatttacccccAACC 89.1 1254 1254_1 CAAATCATTTACCCCCAA CaaatcatttacccCCAA92 1255 1255_1 CCAAATCATTTACCCCCAA CcaaatcatttaccccCAA 91 1256 1256_1ACCAAATCATTTACCCCCA AccaaatcatttaccccCA 89.9 1257 1257_1TACCAAATCATTTACCCCC TaccaaatcatttacccCC 84 1258 1258_1 ACCAAATCATTTACCCCACcaaatcatttacCCC 69.9 1259 1259_1 TACCAAATCATTTACCCC TACcaaatcatttaccCC56.3 1260 1260_1 CTACCAAATCATTTACCCC CtaccaaatcatttaccCC 94 1261 1261_1TACCAAATCATTTACCC TAccaaatcatttACCC 68.9 1262 1262_1 CTACCAAATCATTTACCCTACcaaatcatttaCC 70.3 1263 1263_1 TGCTACCAAATCATTTACCTgctaccaaatcattTACC 79 1264 1264_1 GCTACCAAATCATTTACC GCtaccaaatcatttACC83.6 1265 1265_1 TGCTACCAAATCATTTAC TGCTaccaaatcatttAC 88.3 1266 1266_1GCTACCAAATCATTTAC GCTaccaaatcattTAC 71.4 1267 1267_1 TGCTACCAAATCATTTATGCtaccaaatcatTTA 79.8 1268 1268_1 CTGCTACCAAATCATTTA CTGctaccaaatcatTTA75.3 1269 1269_1 ACTGCTACCAAATCATTT ACTGctaccaaatcatTT 83.4 1270 1270_1CTGCTACCAAATCATTT CTGCtaccaaatcatTT 83 1271 1271_1 ACTGCTACCAAATCATTACTGctaccaaatcaTT 71.1 1272 1272_1 CACTTTGCCATAATCAA CActttgccataaTCAA26 1273 1273_1 TTATCTCAAACTATCCCCA TTAtctcaaactatcccCA 92.9 1274 1274_1ATCTCAAACTATCCCCA ATctcaaactatccCCA 72.3 1275 1275_1CTTATCTCAAACTATCCCCA CttatctcaaactatcccCA 85.5 1276 1276_1TATCTCAAACTATCCCC TatctcaaactatcCCC 79.8 1277 1277_1 CTTATCTCAAACTATCCCCCTtatctcaaactatccCC 84 1278 1278_1 TTATCTCAAACTATCCCC TTAtctcaaactatccCC89.7 1279 1279_1 CTTATCTCAAACTATCCC CttatctcaaactaTCCC 83.5 1280 1280_1CCTTATCTCAAACTATCCC CcttatctcaaactatcCC 87.6 1279 1279_2CTTATCTCAAACTATCCC CTtatctcaaactatCCC 76.9 1281 1281_1 TTATCTCAAACTATCCCTtatctcaaactaTCCC 84.7 1282 1282_1 CTTATCTCAAACTATCC CTTatctcaaactaTCC78.3 1283 1283_1 CCCTTATCTCAAACTATCC CccttatctcaaactaTCC 76.4 12841284_1 CCTTATCTCAAACTATCC CCTtatctcaaactatCC 69.3 1285 1285_1CCTTATCTCAAACTATC CCttatctcaaacTATC 75.9 1286 1286_1 GCCCTTATCTCAAACTATCGCccttatctcaaactaTC 76.6 1287 1287_1 CCCTTATCTCAAACTATCCCcttatctcaaacTATC 67.2 1288 1288_1 TGCCCTTATCTCAAACTATTgcccttatctcaaacTAT 90.5 1289 1289_1 GCCCTTATCTCAAACTATGCccttatctcaaacTAT 71.9 1290 1290_1 CCCTTATCTCAAACTAT CCCTtatctcaaactAT77.7 1291 1291_1 GCCCTTATCTCAAACTA GCccttatctcaaacTA 68.4 1292 1292_1TGCCCTTATCTCAAACTA TgcccttatctcaaaCTA 81.5 1293 1293_1 TGCCCTTATCTCAAACTTGcccttatctcaaaCT 75.7 1294 1294_1 TTGCCCTTATCTCAAAC TTGCccttatctcaaAC89 1295 1295_1 CTTGCCCTTATCTCAA CTtgcccttatcTCAA 48.2 1296 1296_1TGAAATCAAACTTCATCA TGAaatcaaacttcaTCA 66.5 1297 1297_1 GGTCACCATACTTAATGGTCaccatacttaAT 89.7 1298 1298_1 TGCTAACACAAATTTCCT TGctaacacaaattTCCT47.3 1299 1299_1 GCTAACACAAATTTCCT GCTaacacaaatttCCT 48.9 1299 1299_2GCTAACACAAATTTCCT GCtaacacaaattTCCT 45.7 1300 1300_1 TTGCTAACACAAATTTCCTTGCtaacacaaatttCC 60.7 1301 1301_1 TGCTAACACAAATTTCC TGCTaacacaaatttCC62.6 1302 1302_1 TTGCTAACACAAATTTC TTGCtaacacaaattTC 72.4 1303 1303_1CCTTTGCTAACACAAAT CCTTtgctaacacaaAT 48.1 1304 1304_1 GTATAACCAATAATAACTAGTAtaaccaataataaCTA 86.1 1305 1305_1 TCTGACATCACACAATTTTCTGacatcacacaatTT 67.8 1306 1306_1 TCTGACATCACACAATT TCTGacatcacacaaTT70.2 1307 1307_1 TATCTGACATCACACAA TATctgacatcacaCAA 69.8 1308 1308_1CTATTCCTTAACCCAAC CTattccttaaccCAAC 77.7 1309 1309_1 GTCTATTCCTTAACCCAACGtctattccttaaccCAAC 86.2 1310 1310_1 GTCTATTCCTTAACCCAAGtctattccttaacCCAA 60.4 1311 1311_1 TCTATTCCTTAACCCAA TCTattccttaaccCAA51 1312 1312_1 GTCTATTCCTTAACCCA GtctattccttaacCCA 67.3 1313 1313_1GTCTATTCCTTAACCC GtctattccttaaCCC 77.4 1314 1314_1 GGTCTATTCCTTAACCGGtctattccttaaCC 83.2 1315 1315_1 AGAACATTTCCTTCTCCT AgaacatttccttctcCT84.2 1316 1316_1 AACTGTCCCAAACAACC AACtgtcccaaacaaCC 75 1317 1317_1TTAGTCTCCCTCATTTTC TtagtctccctcattTTC 72.4 1318 1318_1 ATTTAGTCTCCCTCATTATttagtctccctCATT 48 1319 1319_1 ATGCATCAAATCTCATA ATGCatcaaatctcaTA83.7 1320 1320_1 CCTAAATAATTTAATCATTAA CCTaaataatttaatcatTAA 94 13211321_1 CCCTAAATAATTTAATCATTA CCCTaaataatttaatcatTA 88.8 1322 1322_1CCCCTAAATAATTTAATCATT CCCctaaataatttaatcATT 80.7 1323 1323_1CCCTAAATAATTTAATCATT CCCTaaataatttaatcaTT 82.2 1324 1324_1CCCTAAATAATTTAATCAT CCCtaaataatttaatCAT 87.1 1325 1325_1CCCCTAAATAATTTAATCA CCCctaaataatttaaTCA 79.9 1326 1326_1CCCTAAATAATTTAATCA CCCtaaataatttaaTCA 82.5 1327 1327_1CCCCTAAATAATTTAATC CCCCtaaataatttaaTC 116 1328 1328_1TCCCCTAAATAATTTAATC TCCCctaaataatttaaTC 109 1329 1329_1TTGCTAATATTTCCAAAA TTGCtaatatttccaaAA 84.2 1330 1330_1 CTTGCTAATATTTCCAACTtgctaatatttCCAA 66.1 1331 1331_1 ACTGTCATCCATATTTCC ActgtcatccatattTCC66.2 1332 1332_1 ACTGTCATCCATATTTC ACTgtcatccatatTTC 48.1 1333 1333_1AATGCCCCACTCTAATAT AATGccccactctaatAT 36.9 1334 1334_1 TGCCCCACTCTAATATTGCcccactctaatAT 52.8 1335 1335_1 ATGCCCCACTCTAATAT ATgccccactctaaTAT43.7 1336 1336_1 AAATGCCCCACTCTAATA AAATgccccactctaaTA 25.7 1337 1337_1ATGCCCCACTCTAATA ATGccccactctaaTA 28.6 1338 1338_1 AATGCCCCACTCTAATAAATGccccactctaaTA 29.9 1339 1339_1 TTAAATGCCCCACTCTA TtaaatgccccactCTA51.3 1340 1340_1 TCTGAAAATTCACTATCT TCTGaaaattcactatCT 35.7 1341 1341_1GTCTACTATATACATCT GTCtactatatacaTCT 30.6 1342 1342_1 AGTCTACTATATACATCTAGTCtactatatacatCT 45.3 1343 1343_1 AGTCTACTATATACATC AGTCtactatatacaTC57 1344 1344_1 GTCTACTATATACATC GTCTactatatacaTC 46.5 1345 1345_1TAGTCTACTATATACATC TAgtctactatataCATC 68.3 1346 1346_1 TAGTCTACTATATACATTAGtctactatataCAT 89 1347 1347_1 CTAGTCTACTATATACAT CTAgtctactatataCAT86.6 1348 1348_1 CTAGTCTACTATATACA CTAGtctactatataCA 88.5 1349 1349_1ACTAGTCTACTATATAC ACTagtctactataTAC 85.1 1350 1350_1 CTAGTCTACTATATACCTAgtctactataTAC 85.3 1351 1351_1 GTATATTCTACCCATAA GTAtattctacccaTAA51.3 1352 1352_1 TGTATATTCTACCCATAA TGTatattctacccaTAA 48.4 1353 1353_1TGTATATTCTACCCATA TGtatattctaccCATA 45.6 1354 1354_1 ATGTATATTCTACCCATAATgtatattctaccCATA 90.2 1355 1355_1 ATGTATATTCTACCCAT ATgtatattctacCCAT51.1 1356 1356_1 GAAAACCACACAATTCCTA GaaaaccacacaattCCTA 58.9 13571357_1 GAAAACCACACAATTCCT GAaaaccacacaatTCCT 56.4 1358 1358_1AGAAAACCACACAATTCCT AGaaaaccacacaattCCT 58.4 1359 1359_1CAGAAAACCACACAATTCC CAGaaaaccacacaatTCC 43.3 1360 1360_1AGAAAACCACACAATTCC AGAaaaccacacaatTCC 47.6 1361 1361_1CCAGAAAACCACACAATTC CCAGaaaaccacacaatTC 26.3 1362 1362_1CCAGAAAACCACACAATT CCAGaaaaccacacaaTT 21 1363 1363_1 TCCAGAAAACCACACAATTCCAgaaaaccacacaAT 47.1 1364 1364_1 TTCCAGAAAACCACACAATTCCagaaaaccacacAA 49.8 1364 1364_2 TTCCAGAAAACCACACAATTCcagaaaaccacaCAA 45.8 1365 1365_1 GATATATCACTAAATCCATGAtatatcactaaatCCAT 27.4 1366 1366_1 GATATATCACTAAATCCAGAtatatcactaaaTCCA 43.7 1367 1367_1 AGATATATCACTAAATCCAAGatatatcactaaaTCCA 37.4 1368 1368_1 AGATATATCACTAAATCCAGAtatatcactaaaTCC 33.6 1369 1369_1 TCATATATAAATTTCTCTATCAtatataaatttctCTA 78 1369 1369_2 TCATATATAAATTTCTCTATCATatataaatttctcTA 73.1 1370 1370_1 TCATATATAAATTTCTCTTCatatataaatttCTCT 27.9 1370 1370_2 TCATATATAAATTTCTCTTCATatataaatttctCT 60.2 1371 1371_1 AAGATCACACAACCATA AAGAtcacacaaccaTA19.8 1372 1372_1 TAAAAGATCACACAACCA TAaaagatcacacaACCA 47.5 1373 1373_1CATCACATAAAAACCCACTT CATcacataaaaacccaCTT 45.4 1374 1374_1CATCACATAAAAACCCACT CAtcacataaaaaccCACT 57.9 1375 1375_1TCATCACATAAAAACCCACT TCatcacataaaaaccCACT 30.1 1376 1376_1CATCACATAAAAACCCAC CAtcacataaaaacCCAC 61.6 1377 1377_1TCATCACATAAAAACCCAC TCatcacataaaaacCCAC 30.6 1378 1378_1GTCATCACATAAAAACCCAC GTCatcacataaaaaccCAC 24.9 1379 1379_1GTCATCACATAAAAACCCA GTCatcacataaaaacCCA 28.7 1380 1380_1TCATCACATAAAAACCCA TCatcacataaaaaCCCA 43.9 1381 1381_1 CATCACATAAAAACCCACAtcacataaaaaCCCA 71.5 1382 1382_1 TCATCACATAAAAACCC TCAtcacataaaaaCCC42.9 1383 1383_1 GTCATCACATAAAAACCC GTCatcacataaaaaCCC 24.9 1384 1384_1AGTCATCACATAAAAACCC AGtcatcacataaaaACCC 35.8 1384 1384_2AGTCATCACATAAAAACCC AGTCatcacataaaaacCC 23 1385 1385_1TAGTCATCACATAAAAACC TAGTcatcacataaaaaCC 36.3 1386 1386_1AGTCATCACATAAAAACC AGTCatcacataaaaaCC 34.9 1387 1387_1 ATGCTAAATACAAATCTATGCtaaatacaaatCT 81 1388 1388_1 GAAACCATTACTACAACCAAGAaaccattactacaaCCAA 20.1 1389 1389_1 GAAACCATTACTACAACCAGAaaccattactacaACCA 15.9 1390 1390_1 ATGAAACCATTACTACAACATGAaaccattactacaAC 45.6 1391 1391_1 CATGAAACCATTACTACACATGaaaccattactaCA 55.9 1392 1392_1 CCATGAAACCATTACTACCCatgaaaccattaCTAC 29.5 1393 1393_1 CTCCCATGAAACCATTA CTCCcatgaaaccatTA73.7 1394 1394_1 TGCTTACTTTATACAAAA TGCTtactttatacaaAA 55.9 1395 1395_1ATGTTAATACTTTTTCCA ATGttaatactttttCCA 92.9 1396 1396_1 CCTAATTTAACCCACAACCTaatttaacccaCAA 32.2 1397 1397_1 ATCCTAATTTAACCCACAAATCctaatttaacccaCAA 38.1 1398 1398_1 TCCTAATTTAACCCACAATCCtaatttaacccaCAA 39.9 1399 1399_1 TAATCCTAATTTAACCCACAATAAtcctaatttaacccaCAA 72.8 1400 1400_1 TAATCCTAATTTAACCCACATAatcctaatttaaccCACA 45 1401 1401_1 AATCCTAATTTAACCCACAAATCctaatttaacccaCA 41.2 1402 1402_1 TCCTAATTTAACCCACA TCCtaatttaacccACA38.3 1403 1403_1 TAATCCTAATTTAACCCAC TAatcctaatttaacCCAC 37.5 14041404_1 ATCCTAATTTAACCCAC ATcctaatttaacCCAC 34.4 1405 1405_1AATCCTAATTTAACCCAC AAtcctaatttaacCCAC 48.2 1406 1406_1TAATCCTAATTTAACCCA TAatcctaatttaaCCCA 56.5 1407 1407_1 AATCCTAATTTAACCCAAAtcctaatttaaCCCA 71.7 1408 1408_1 GTAATCCTAATTTAACCCAGtaatcctaatttaaCCCA 63.6 1409 1409_1 TAATCCTAATTTAACCC TAatcctaatttaACCC56.5 1410 1410_1 GTAATCCTAATTTAACCC GTaatcctaatttaACCC 44 1411 1411_1AGTAATCCTAATTTAACCC AGtaatcctaatttaaCCC 66.2 1410 1410_2GTAATCCTAATTTAACCC GTAatcctaatttaaCCC 34.2 1412 1412_1AGTAATCCTAATTTAACC AGTAatcctaatttaaCC 42.7 1413 1413_1TCATTTATCACTACCACA TCAtttatcactaccACA 26.5 1414 1414_1CATCATTTATCACTACCACA CatcatttatcactacCACA 46 1415 1415_1CATTTATCACTACCACA CAtttatcactacCACA 19.4 1416 1416_1 ATCATTTATCACTACCACAATcatttatcactacCACA 16.8 1416 1416_2 ATCATTTATCACTACCACAATCAtttatcactaccaCA 14.1 1417 1417_1 ACATCATTTATCACTACCACAACatcatttatcactaccACA 53.4 1418 1418_1 TCATTTATCACTACCACTCAtttatcactacCAC 18.9 1419 1419_1 ATCATTTATCACTACCAC ATcatttatcactaCCAC21.8 1420 1420_1 CATCATTTATCACTACCAC CATcatttatcactacCAC 25.1 14211421_1 AACATCATTTATCACTACCAC AACatcatttatcactacCAC 30.5 1421 1421_2AACATCATTTATCACTACCAC AacatcatttatcactaCCAC 40.4 1420 1420_2CATCATTTATCACTACCAC CatcatttatcactaCCAC 34.3 1422 1422_1AACATCATTTATCACTACCA AAcatcatttatcactACCA 34 1423 1423_1CATCATTTATCACTACCA CATCatttatcactacCA 11.3 1424 1424_1TAACATCATTTATCACTACCA TAacatcatttatcactaCCA 63.1 1425 1425_1ACATCATTTATCACTACCA ACATcatttatcactacCA 19 1422 1422_2AACATCATTTATCACTACCA AACatcatttatcactaCCA 25 1424 1424_2TAACATCATTTATCACTACCA TaacatcatttatcactACCA 61.3 1425 1425_2ACATCATTTATCACTACCA ACatcatttatcactACCA 23.5 1426 1426_1TAACATCATTTATCACTACC TAACatcatttatcactaCC 33.6 1427 1427_1ACATCATTTATCACTACC ACatcatttatcacTACC 32.3 1428 1428_1TTAACATCATTTATCACTACC TTAacatcatttatcactaCC 75.5 1429 1429_1AACATCATTTATCACTACC AACAtcatttatcactaCC 37.3 1430 1430_1TTAACATCATTTATCACTAC TTaacatcatttatcaCTAC 69.1 1431 1431_1TAACATCATTTATCACTAC TAacatcatttatcaCTAC 66.6 1432 1432_1ATTAACATCATTTATCACTAC ATtaacatcatttatcaCTAC 84.2 1432 1432_2ATTAACATCATTTATCACTAC ATtaacatcAtttatcaCTAC 62.8 1433 1433_1ATTAACATCATTTATCACTA ATTaacatcatttatcaCTA 81.3 1434 1434_1TTAACATCATTTATCACTA TTAacatcatttatcaCTA 74.5 1435 1435_1TAATTAACATCATTTATCACT TAattaacatcatttatCACT 84.3 1435 1435_2TAATTAACATCATTTATCACT TAattaacaTcatttatCACT 43.3 1436 1436_1CTAATTAACATCATTTATCAC CTaattaacatcatttaTCAC 81.4 1436 1436_2CTAATTAACATCATTTATCAC CTaattaacAtcatttaTCAC 46.7 1437 1437_1CCTAATTAACATCATTTATCA CCtaattaacatcatttaTCA 93.8 1438 1438_1CTAATTAACATCATTTATCA CTAattaacatcatttaTCA 89.6 1439 1439_1CCTAATTAACATCATTTATC CCTAattaacatcatttaTC 69.4 1440 1440_1CCCTAATTAACATCATTTATC CCctaattaacatcatttATC 86.3 1441 1441_1CCTAATTAACATCATTTAT CCTaattaacatcattTAT 87.4 1442 1442_1CCTAATTAACATCATTTA CCTAattaacatcattTA 66 1443 1443_1 CCCTAATTAACATCATTTACCCtaattaacatcattTA 88.7 1444 1444_1 GCCCTAATTAACATCATTTGCCctaattaacatcatTT 87.9 1445 1445_1 CCCTAATTAACATCATTTCCCTaattaacatcatTT 75.6 1446 1446_1 CGGCCCTAATTAACAT CGGCcctaattaacAT103 1447 1447_1 CTCGGCCCTAATTAA CTCggccctaatTAA 57.4 1448 1448_1CACATATAACATATAAACACA CACAtataacatataaacaCA 61.7 1449 1449_1TCACATATAACATATAAACAC TCAcatataacatataaaCAC 43.6 1450 1450_1ACTATCACATATAACATATA ACTAtcacatataacataTA 58.5 1451 1451_1CACTATCACATATAACATATA CACTatcacatataacataTA 28.1 1452 1452_1CACTATCACATATAACATAT CACtatcacatataacaTAT 52 1453 1453_1CACTATCACATATAACATA CACTatcacatataacaTA 24.3 1454 1454_1CACTATCACATATAACAT CACtatcacatataaCAT 40.1 1455 1455_1 CACTATCACATATAACACACTatcacatataaCA 27 1456 1456_1 CAAAGTTTTCCCATTAC CAaagttttcccaTTAC 211457 1457_1 ACAAAGTTTTCCCATTA ACAaagttttcccaTTA 20.5 1458 1458_1TCAGTCCAACATAACTC TCAGtccaacataacTC 15.2 1459 1459_1 CAGTCCAACATAACTCCAGtccaacataaCTC 23.5 1460 1460_1 ATCAGTCCAACATAACTC ATCAgtccaacataacTC13.7 1461 1461_1 ATCAGTCCAACATAACT ATCAgtccaacataaCT 15.9 1462 1462_1TAAACATTAAACCCTCCCAAA TAaacattaaaccctccCAAA 87 1463 1463_1AACATTAAACCCTCCCAA AAcattaaaccctcCCAA 68.4 1464 1464_1TAAACATTAAACCCTCCCAA TaaacattaaaccctcCCAA 79.2 1465 1465_1AAACATTAAACCCTCCCAA AAacattaaaccctcCCAA 70.8 1466 1466_1TATAAACATTAAACCCTCCCA TAtaaacattaaaccctccCA 94 1467 1467_1AACATTAAACCCTCCC AAcattaaacccTCCC 78.3 1468 1468_1 AAACATTAAACCCTCCCAAacattaaacccTCCC 89.4 1469 1469_1 TAAACATTAAACCCTCCC TAAacattaaaccctCCC72.9 1470 1470_1 ATAAACATTAAACCCTCCC AtaaacattaaacccTCCC 86 1471 1471_1TATAAACATTAAACCCTCC TAtaaacattaaaccCTCC 91.1 1472 1472_1TAAACATTAAACCCTCC TAaacattaaaccCTCC 82.2 1473 1473_1ACTATAAACATTAAACCCTCC ActataaacattaaaccCTCC 86.5 1474 1474_1ATAAACATTAAACCCTCC ATaaacattaaaccCTCC 88.4 1475 1475_1AACTATAAACATTAAACCCTC AActataaacattaaacCCTC 92.6 1476 1476_1CTATAAACATTAAACCCTC CTataaacattaaacCCTC 82.9 1477 1477_1ACTATAAACATTAAACCCTC ACtataaacattaaacCCTC 89.8 1478 1478_1AAACTATAAACATTAAACCCT AAactataaacattaaaCCCT 98.9 1479 1479_1CTATAAACATTAAACCCT CTataaacattaaaCCCT 82.2 1480 1480_1ACTATAAACATTAAACCCT ACtataaacattaaaCCCT 86.6 1481 1481_1AACTATAAACATTAAACCCT AActataaacattaaaCCCT 89.5 1482 1482_1GCTTTAAACTATAAACATT GCtttaaactataaaCATT 58.2 1483 1483_1TGCTTTAAACTATAAACA TGCTttaaactataaaCA 57.2 1484 1484_1 CAGATTTATCACTATTACAGAtttatcactatTA 15.4 1485 1485_1 TCACAGCCTATCACCAC TCacagcctatcacCAC47.3 1485 1485_2 TCACAGCCTATCACCAC TCAcagcctatcaccAC 46.3 1486 1486_1ATCACAGCCTATCACCA AtcacagcctatcACCA 56.9 1486 1486_2 ATCACAGCCTATCACCAATCacagcctatcacCA 23.7 1487 1487_1 AATCACAGCCTATCACC AATCacagcctatcaCC32.9 1487 1487_2 AATCACAGCCTATCACC AatcacagcctatCACC 52.2 1488 1488_1ATCACAGCCTATCACC AtcacagcctatCACC 60.1 1489 1489_1 GCGTCACCCAAATCACGCgtcacccaaatCAC 11 1490 1490_1 AGCGTCACCCAAATCA AGmcgtcacccaaaTCA 17.41491 1491_1 AGCGTCACCCAAATC AGmcgtcacccaAATC 18.8 1492 1492_1CAGATCCTAAAATCACT CAGAtcctaaaatcaCT 71.8 1493 1493_1 TCAGATCCTAAAATCACTCAgatcctaaaatCAC 66.2 1494 1494_1 AGTAAAACCAATCATCAT AGTaaaaccaatcatCAT30.8 1495 1495_1 AGTAAAACCAATCATCA AGTaaaaccaatcaTCA 24.2 1496 1496_1CCCTTCCATCTCTACTAAAA CccttccatctctactaaAA 89.7 1497 1497_1ATAACTACATAACAAACCCA ATaactacataacaaaCCCA 69.1 1498 1498_1AATAACTACATAACAAACCCA AAtaactacataacaaaCCCA 77.8 1499 1499_1AACTACATAACAAACCCA AActacataacaaaCCCA 62.9 1500 1500_1TAACTACATAACAAACCCA TAactacataacaaaCCCA 65 1501 1501_1 ACTACATAACAAACCCAACtacataacaaaCCCA 60.4 1502 1502_1 CAATAACTACATAACAAACCCCAAtaactacataacaaaCCC 72.6 1503 1503_1 ATAACTACATAACAAACCCATAactacataacaaaCCC 60.2 1504 1504_1 ACAATAACTACATAACAAACCACAataactacataacaaACC 78.5 1504 1504_2 ACAATAACTACATAACAAACCACAAtaactacataacaaaCC 80.9 1505 1505_1 TGAATTCACAATAACTACATGaattcacaataacTACA 38.1 1506 1506_1 GCACATTTTTCTTAAACTGCACatttttcttaaaCT 62.2 1507 1507_1 GCTATACCTAAAACAATCTGCTatacctaaaacaaTCT 62.2 1508 1508_1 GCTATACCTAAAACAATCGCTAtacctaaaacaaTC 68.9 1509 1509_1 CCCTTGTAACTAAAAAT CCCTtgtaactaaaaAT100 1510 1510_1 CCCCTTGTAACTAAAAA CCCCttgtaactaaaAA 86.1 1511 1511_1CCCCTTGTAACTAAAA CCCCttgtaactaaAA 101 1512 1512_1 ACCCCTTGTAACTAAAACCCcttgtaactaAA 88.8 1513 1513_1 CACCCCTTGTAACTAA CAccccttgtaaCTAA 80.41514 1514_1 ACACCCCTTGTAACTA ACACcccttgtaacTA 72.4 1515 1515_1GCTAAAACTAATCATCT GCTaaaactaatcaTCT 72.2 1516 1516_1 GGCTAAAACTAATCATGGCtaaaactaatCAT 70.8 1517 1517_1 TTACCCTTCATATATACATCTTtacccttcatatatacaTCT 89.4 1518 1518_1 ATTACCCTTCATATATACATCAttacccttcatatataCATC 82.4 1519 1519_1 TTACCCTTCATATATACATCTTAcccttcatatatacATC 56.3 1520 1520_1 CATTACCCTTCATATATACATCAttacccttcatatataCAT 84.2 1521 1521_1 TTACCCTTCATATATACATTTAcccttcatatataCAT 55.3 1522 1522_1 ATTACCCTTCATATATACATATTacccttcatatataCAT 49.3 1523 1523_1 ACATTACCCTTCATATATACAACAttacccttcatatataCA 55.2 1523 1523_2 ACATTACCCTTCATATATACAAcattacccttcatataTACA 63.4 1524 1524_1 TTACCCTTCATATATACATTACccttcatatataCA 46.9 1525 1525_1 CATTACCCTTCATATATACACattacccttcatataTACA 66 1526 1526_1 ATTACCCTTCATATATACAATTAcccttcatatataCA 36.7 1527 1527_1 ATTACCCTTCATATATACATTacccttcatataTAC 46.6 1528 1528_1 TTACCCTTCATATATAC TTAcccttcatataTAC56.9 1529 1529_1 CATTACCCTTCATATATAC CATtacccttcatataTAC 63.4 15301530_1 ACATTACCCTTCATATATAC ACAttacccttcatataTAC 34.5 1531 1531_1TACATTACCCTTCATATATAC TAcattacccttcatataTAC 76.9 1532 1532_1CATTACCCTTCATATATA CAttacccttcataTATA 76.5 1533 1533_1TACATTACCCTTCATATATA TACattacccttcatatATA 36.5 1534 1534_1ATTACCCTTCATATATA ATtacccttcataTATA 78 1535 1535_1 ACATTACCCTTCATATATAACattacccttcataTATA 59.5 1536 1536_1 CATTACCCTTCATATAT CATtacccttcataTAT73.7 1537 1537_1 ACATTACCCTTCATATAT ACAttacccttcataTAT 46.1 1538 1538_1TACATTACCCTTCATATAT TACattacccttcataTAT 36.9 1539 1539_1ACATTACCCTTCATATA ACattacccttcaTATA 54.2 1540 1540_1 TACATTACCCTTCATATATAcattacccttcaTATA 71.5 1541 1541_1 TACATTACCCTTCATAT TACattacccttcaTAT34.5 1542 1542_1 GATTCTTATACTTACTA GATtcttatacttaCTA 46.2 1543 1543_1TGATTCTTATACTTACT TGattcttatactTACT 45.7 1544 1544_1 ATGATTCTTATACTTACTATGAttcttatacttaCT 54 1545 1545_1 GCCTCATTTTTACCTTT GCctcalllllaccTTT82.6 1546 1546_1 ACCAATCTTCTATTTTA ACCAatcttctatttTA 94.8 1547 1547_1CAACCAATCTTCTATTTTA CAACcaatcttctatttTA 90.3 1548 1548_1GCAACCAATCTTCTATTTT GCAAccaatcttctattTT 88.3 1549 1549_1GCAACCAATCTTCTATTT GCAaccaatcttctaTTT 85 1550 1550_1 GCAACCAATCTTCTATTGCaaccaatcttcTATT 87.3 1551 1551_1 TGCAACCAATCTTCTATT TGCaaccaatcttctaTT90.2 1552 1552_1 TAACTGCAACCAATCTT TAactgcaaccaaTCTT 88.2 1553 1553_1TGAATACAACACACATCA TGAatacaacacacaTCA 97.4 1554 1554_1ATGAATACAACACACATCA ATGAatacaacacacatCA 84.4 1555 1555_1TAAAAATATAACTACTCCT TAaaaatataactacTCCT 99.8 1556 1556_1GTAAAAATATAACTACTCC GTaaaaatataactaCTCC 93.7 1557 1557_1TCAACTGATACCCACAA TCAactgatacccaCAA 57.7 1558 1558_1 TGTCTTAACATTTTTCTTTGTCttaacatttttcTT 63.1 1559 1559_1 CCACTTCAAACTTTTAATTAACCAcftcaaacttttaatTAA 85 1560 1560_1 CCACTTCAAACTTTTAATTACCACttcaaacttttaatTA 84.9 1561 1561_1 CCCACTTCAAACTTTTAATTACCcacttcaaacttttaaTTA 88.7 1562 1562_1 CCACTTCAAACTTTTAATTCCACftcaaacttttaaTT 79.1 1563 1563_1 CCCACTTCAAACTTTTAATTCCCacftcaaacttttaaTT 86.2 1564 1564_1 ACCCACTTCAAACTTTTAATTACCcacftcaaacttttaaTT 100 1565 1565_1 CCACTTCAAACTTTTAATCCACttcaaacttttaAT 85.3 1566 1566_1 ACCCACTTCAAACTTTTAATACCcacftcaaacttttAAT 88.8 1567 1567_1 AACCCACTTCAAACTTTTAATAACCcacttcaaacttttaAT 92.3 1568 1568_1 CCCACTTCAAACTTTTAACCCacttcaaactttTAA 79.9 1569 1569_1 ACCCACTTCAAACTTTTAAACCcacttcaaactaTAA 82.5 1570 1570_1 CCCACTTCAAACTTTTA CCCacttcaaactttTA79.6 1571 1571_1 ACCCACTTCAAACTTTTA ACCcacttcaaacttTTA 77.2 1572 1572_1AACCCACTTCAAACTTTTA AACCcacttcaaactttTA 86.2 1573 1573_1ACCCACTTCAAACTTTT ACCCacttcaaacttTT 93.3 1574 1574_1 AACCCACTTCAAACTTTTAACCcacttcaaacttTT 82.7 1575 1575_1 AACCCACTTCAAACTTT AACCcacttcaaactTT85.8 1576 1576_1 GGACTCTATTAATCAA GGActctattaatCAA 91.7 1577 1577_1GAATATTCTACTCTTCT GAatattctactcTTCT 95.3 1578 1578_1 CTGTATTTACCAATTCAACTGtatttaccaattCAA 90.8 1579 1579_1 CTGTATTTACCAATTCA CTGTatttaccaattCA88.7 1580 1580_1 ACTGTATTTACCAATTCA ACTGtatttaccaattCA 97.3 1581 1581_1ACTGTATTTACCAATTC ACTGtatttaccaatTC 104 1582 1582_1 CACTGTATTTACCAATTCACTgtatttaccaaTT 91.1 1583 1583_1 TCACTGTATTTACCAAT TCACtgtatttaccaAT98.6 1584 1584_1 CCAACTACTTTACTTTTCAAA CCaactactttacttttCAAA 84.3 15851585_1 CCAACTACTTTACTTTTCAA CCaactactttactttTCAA 80 1586 1586_1ACCAACTACTTTACTTTTCAA ACcaactactttactttTCAA 85.1 1585 1585_2CCAACTACTTTACTTTTCAA CCAactactttacttttCAA 75.2 1587 1587_1CCAACTACTTTACTTTTCA CCAactactttacttttCA 71.9 1588 1588_1TACCAACTACTTTACTTTTCA TaccaactactttacttTTCA 82.8 1587 1587_2CCAACTACTTTACTTTTCA CCAactactttactttTCA 67.7 1589 1589_1ACCAACTACTTTACTTTTCA ACcaactactttactttTCA 84 1590 1590_1TACCAACTACTTTACTTTTC TACcaactactttacttTTC 75.3 1591 1591_1GTACCAACTACTTTACTTT GTACcaactactttactTT 75.8 1592 1592_1GTACCAACTACTTTACTT GTAccaactactttaCTT 65.7 1593 1593_1 GTACCAACTACTTTACTGTACcaactactttaCT 74.5 1594 1594_1 TGTACCAACTACTTTACT TGtaccaactacttTACT87.1 1595 1595_1 TTGTACCAACTACTTTAC TTGtaccaactacttTAC 73.3 1596 1596_1GTACCAACTACTTTAC GTAccaactacttTAC 72.5 1597 1597_1 TGTACCAACTACTTTACTGTaccaactacttTAC 66 1598 1598_1 TTGTACCAACTACTTTA TTGTaccaactacttTA49.3 1599 1599_1 ATTTCATTTTTCTTTTAATA ATTtcatttttcttttaATA 98.6 15991599_2 ATTTCATTTTTCTTTTAATA ATTTcatttttcttttaaTA 90.7 1600 1600_1CCTAATTTCATTTTTCTTTT CCtaatttcatttttcTTTT 69.2 1601 1601_1TCCTAATTTCATTTTTCTTT TCctaatttcatttttCTTT 47 1602 1602_1TTCTTCATTATACCATCAAAT TTCTtcattataccatcaaAT 29.4 1603 1603_1TTTCTTCATTATACCATCAAA TTTCttcattataccatcaAA 24.1 1604 1604_1TTTTCTTCATTATACCATCAA TTttcttcattataccaTCAA 14.3 1605 1605_1TCTTCATTATACCATCAA TCttcattataccaTCAA 5.02 1606 1606_1TTTCTTCATTATACCATCAA TTtcttcattataccaTCAA 21.2 1607 1607_1TTCTTCATTATACCATCAA TTCttcattataccatCAA 5.83 1608 1608_1ATATTTTCTTCATTATACCAT AtattttcttcattataCCAT 76.1 1609 1609_1ATATTTTCTTCATTATACCA ATattttcttcattataCCA 40.2 1610 1610_1AATATTTTCTTCATTATACCA AATattacttcattataCCA 37 1611 1611_1AAATATTTTCTTCATTATACC AAatattttcttcattaTACC 23.4 1612 1612_1ATATTTTCTTCATTATACC ATattttcttcattaTACC 14.2 1613 1613_1AATATTTTCTTCATTATACC AATAttttcttcattataCC 68 1614 1614_1TAAATATTTTCTTCATTATA TAaatattttcttcatTATA 96.8 1615 1615_1TTTTCCTTCATCTACTTCT TTTtccttcatctacttCT 42.8 1616 1616_1ATTTTCCTTCATCTACTTCT ATtttccttcatctacttCT 76 1617 1617_1AATTTTCCTTCATCTACTTC AATTttccttcatctactTC 54.9 1618 1618_1AGAATTTTCCTTCATCTA AgaattttccttcaTCTA 58 1619 1619_1 CAGAATTTTCCTTCATCTCAgaattttccttcATCT 23.5 1620 1620_1 TCAGAATTTTCCTTCATCTCAgaattttccttcaTC 29.7 1621 1621_1 CTAGAAATATCTCACATTCTAGaaatatctcacaTT 64.6 1622 1622_1 CTAGAAATATCTCACAT CTAgaaatatctcaCAT75.5 1623 1623_1 ACTAGAAATATCTCACA ACTAgaaatatctcaCA 53.2 1624 1624_1ATTAGCCATTAATCTAT ATtagccattaatCTAT 71.9 1625 1625_1 TTGTTACAAAATAATCCATTgttacaaaataaTCCA 12 1625 1625_2 TTGTTACAAAATAATCCA TTGttacaaaataatCCA23.8 1626 1626_1 TTATTTTTTACATTAACTA TTAttttttacattaaCTA 92.1 16271627_1 TGCCAAAATACTAACATCA TGCcaaaatactaacaTCA 32 1628 1628_1GCCAAAATACTAACATCA GCCaaaatactaacaTCA 27.8 1629 1629_1TGCCAAAATACTAACATC TGCCaaaatactaacaTC 61.5 1630 1630_1 GAGTACAACACTTACAGAGTacaacacttaCA 31.8 1631 1631_1 CACATCCATTCATTTTAT CACatccattcatttTAT30.6 1632 1632_1 CCACATCCATTCATTTTAT CCAcatccattcattttAT 21.7 16331633_1 CCACATCCATTCATTTTA CCacatccattcattTTA 20 1634 1634_1TATGCCACATCCATTCAT TatgccacatccattCAT 47 1635 1635_1 TTATGCCACATCCATTCATtatgccacatccaTTCA 20.7 1636 1636_1 TATGCCACATCCATTCA TAtgccacatccattCA43.3 1637 1637_1 TTATGCCACATCCATTC TtatgccacatccATTC 19.5 1638 1638_1ATTATGCCACATCCATT ATtatgccacatcCATT 25.1 1639 1639_1 AGTTTCATATTTTTAATCAGTttcatatttttaATC 65.9 1640 1640_1 ATCACTGCACACTTTCC ATCactgcacactttCC12.9 1641 1641_1 AAGCTCTTTCCAAATTCT AAGCtctttccaaattCT 34.6 1642 1642_1TAGTTCTTAACTCTTCTC TagttcttaactctTCTC 19.2 1643 1643_1 TTAGTTCTTAACTCTTCTTAGttcttaactctTC 18 1644 1644_1 AGCTTCAAATACTCAAA AGCTtcaaatactcaAA74.5 1645 1645_1 TTTCAAAGCCACACCTA TttcaaagccacaCCTA 66.9 1646 1646_1AATATCCTCATTACCCATT AATAtcctcattacccaTT 52.3 1647 1647_1TATCCTCATTACCCATT TAtcctcattaccCATT 53.4 1647 1647_2 TATCCTCATTACCCATTTATCctcattacccaTT 22.3 1648 1648_1 ATATCCTCATTACCCATT ATAtcctcattacccATT55.8 1649 1649_1 AATATCCTCATTACCCAT AAtatcctcattacCCAT 46.1 1650 1650_1TAATATCCTCATTACCCAT TAAtatcctcattaccCAT 58.3 1651 1651_1TTAATATCCTCATTACCCAT TTaatatcctcattaccCAT 61.8 1652 1652_1ATATCCTCATTACCCAT ATAtcctcattaccCAT 56.2 1653 1653_1 AATATCCTCATTACCCAAAtatcctcattaCCCA 49.7 1654 1654_1 TAATATCCTCATTACCCA TAATatcctcattaccCA45.6 1655 1655_1 TTTAATATCCTCATTACCCA TttaatatcctcattacCCA 67.5 16561656_1 TTAATATCCTCATTACCCA TTaatatcctcattacCCA 36 1656 1656_2TTAATATCCTCATTACCCA TTAAtatcctcattaccCA 57.9 1654 1654_2TAATATCCTCATTACCCA TAAtatcctcattacCCA 40 1653 1653_2 AATATCCTCATTACCCAAATatcctcattacCCA 44.8 1657 1657_1 ATTTAATATCCTCATTACCCAtttaatatcctcattaCCC 59.9 1658 1658_1 TAATATCCTCATTACCCTAATatcctcattacCC 32.9 1659 1659_1 TTAATATCCTCATTACCC TTAAtatcctcattacCC42 1660 1660_1 TTTAATATCCTCATTACCC TttaatatcctcattACCC 41.1 1661 1661_1AATTTAATATCCTCATTACCC AatttaatatcctcattaCCC 61 1662 1662_1TTTAATATCCTCATTACC TTTAatatcctcattaCC 60.6 1663 1663_1AATTTAATATCCTCATTACC AAtttaatatcctcatTACC 58.8 1664 1664_1TTAATATCCTCATTACC TTaatatcctcatTACC 42.3 1665 1665_1AAATTTAATATCCTCATTACC AAatttaatatcctcatTACC 55.9 1666 1666_1ATTTAATATCCTCATTACC ATttaatatcctcatTACC 55.5 1667 1667_1TAAATTTAATATCCTCATTAC TAaatttaatatcctcaTTAC 78 1668 1668_1TTAAATTTAATATCCTCATTA TTAaatttaatatcctcaTTA 95.2 1669 1669_1CTTAAATTTAATATCCTCATT CTtaaatttaatatcctCATT 73.2 1670 1670_1TCTTAAATTTAATATCCTCAT TCttaaatttaatatccTCAT 46.8 1671 1671_1TCTTAAATTTAATATCCTCA TCttaaatttaatatcCTCA 29.8 1672 1672_1TTCTTAAATTTAATATCCTCA TTCttaaatttaatatccTCA 35 1673 1673_1TTCTTAAATTTAATATCCTC TTcttaaatttaatatCCTC 36.2 1674 1674_1TCTTAAATTTAATATCCTC TCttaaatttaatatCCTC 25.1 1675 1675_1TTCTTAAATTTAATATCCT TTCttaaatttaatatCCT 46.9 1676 1676_1TCTTAAATTTAATATCCT TCttaaatttaataTCCT 50.9 1677 1677_1 AATAGCCTTTATTCTACAAtagcctttattCTAC 33.6 1678 1678_1 CAGCAACAATTATTAATA CAGCaacaattattaaTA70.5 1679 1679_1 CCAGCAACAATTATTAAT CCAGcaacaattattaAT 64.2 1680 1680_1ACCAGCAACAATTATTAA ACCagcaacaattatTAA 20.5 1680 1680_2ACCAGCAACAATTATTAA ACCAgcaacaattattAA 39.7 1681 1681_1 ACCAGCAACAATTATTAACCAgcaacaattatTA 39.4 1682 1682_1 TACCAGCAACAATTATT TACCagcaacaattaTT26.4 1683 1683_1 CCCCAAATCTAAAACACTTC CCccaaatctaaaacacTTC 79.4 16841684_1 AACCCCAAATCTAAAACACTT AACCccaaatctaaaacacTT 82 1685 1685_1CCCCAAATCTAAAACACTT CCCcaaatctaaaacacTT 86.4 1686 1686_1AACCCCAAATCTAAAACACT AACCccaaatctaaaacaCT 75.2 1687 1687_1ACCCCAAATCTAAAACACT ACcccaaatctaaaaCACT 72.5 1688 1688_1ACCCCAAATCTAAAACAC ACCccaaatctaaaaCAC 80.9 1689 1689_1GCAAATATTCACAAATCCT GCAaatattcacaaatCCT 20.7 1689 1689_2GCAAATATTCACAAATCCT GCaaatattcacaaaTCCT 29.3 1690 1690_1ACTATTTAACACACATTATCA ACTatttaacacacattaTCA 36.6 1691 1691_1CTATTTAACACACATTATCA CTAtttaacacacattaTCA 49.6 1692 1692_1TACTATTTAACACACATTATC TACTatttaacacacattaTC 52.4 1693 1693_1ACTATTTAACACACATTATC ACTAtttaacacacattaTC 51.8 1694 1694_1TACTATTTAACACACATTAT TACtatttaacacacatTAT 91.1 1695 1695_1CTACTATTTAACACACATTAT CTActatttaacacacatTAT 72.7 1696 1696_1CTACTATTTAACACACATTA CTACtatttaacacacatTA 47.4 1697 1697_1ACTACTATTTAACACACATTA ACTActatttaacacacatTA 38.3 1698 1698_1CTACTATTTAACACACATT CTACtatttaacacacaTT 41.6 1699 1699_1ACTACTATTTAACACACATT ACtactatttaacacaCATT 40.3 1700 1700_1ACTACTATTTAACACACAT ACTactatttaacacaCAT 36.8 1701 1701_1CTACTATTTAACACACA CTACtatttaacacaCA 45.9 1702 1702_1 ACTACTATTTAACACACAACTActatttaacacaCA 32.6 1703 1703_1 TATAGACCCTTAATATT TATAgacccttaataTT41.4 1704 1704_1 TTATAGACCCTTAATAT TTAtagacccttaaTAT 68.5 1705 1705_1CATCACAAAATAACCTATCAT CAtcacaaaataacctaTCAT 86.8 1706 1706_1TCATCACAAAATAACCTATCA TCAtcacaaaataacctaTCA 67.4 1707 1707_1TTCATCACAAAATAACCTATC TTCAtcacaaaataacctaTC 49 1708 1708_1TTCATCACAAAATAACCTA TTcatcacaaaataaCCTA 76.4 1709 1709_1TTTCATCACAAAATAACCTA TTtcatcacaaaataaCCTA 88.6 1710 1710_1TCATCACAAAATAACCTA TCatcacaaaataaCCTA 59.2 1711 1711_1TTTTCATCACAAAATAACCTA TTttcatcacaaaataaCCTA 86.1 1712 1712_1ATTTTCATCACAAAATAACCT ATTttcatcacaaaataaCCT 64.8 1713 1713_1TATTTTCATCACAAAATAACC TATTttcatcacaaaataaCC 76.9 1713 1713_2TATTTTCATCACAAAATAACC TATTttcatcaCaaaataaCC 56 1714 1714_1GTATTTTCATCACAAAATA GTAT1f1catcacaaaaTA 47 1715 1715_1 TTACCTAGATCACTCCTtacctagatcaCTCC 73.1 1716 1716_1 CTTACCTAGATCACTC CTTacctagatcaCTC 81.51717 1717_1 CCTTACCTAGATCACT CCTtacctagatcaCT 95.9 1718 1718_1TAACTGCTCCTTAATCC TAActgctccttaatCC 34.8 1719 1719_1 TCTAGCAATCCTCTCCTTCtagcaatcctctcCT 64.2 1720 1720_1 TTCTAGCAATCCTCTCC TtctagcaatcctcTCC70.4 1721 1721_1 TTTTCACCTACTAATATTCAT TTttcacctactaatatTCAT 55.3 17221722_1 TTTCACCTACTAATATTCAT TTtcacctactaatatTCAT 66.2 1723 1723_1TTCACCTACTAATATTCAT TTCacctactaatattCAT 17.2 1724 1724_1TCACCTACTAATATTCAT TCAcctactaatattCAT 23.5 1725 1725_1 TCACCTACTAATATTCATCAcctactaatatTCA 21.1 1726 1726_1 TTTCACCTACTAATATTCATTTCacctactaatattCA 16.7 1727 1727_1 TTTTCACCTACTAATATTCATTttcacctactaataTTCA 31.3 1728 1728_1 TTTTTCACCTACTAATATTCATTtttcacctactaataTTCA 45.3 1729 1729_1 TTCACCTACTAATATTCATTCAcctactaatattCA 24.7 1730 1730_1 ATTTTTCACCTACTAATATTCATTMcacctactaataTTC 48.5 1731 1731_1 TTTTTCACCTACTAATATTCTTTttcacctactaataTTC 31.5 1732 1732_1 TATTTTTCACCTACTAATATTTAtttttcacctactaaTATT 90.2 1733 1733_1 TATTTTTCACCTACTAATATTATttttcacctactaaTAT 89.1 1734 1734_1 TTATTTTTCACCTACTAATATTTAtttttcacctactaaTAT 86.1 1735 1735_1 TTATTTTTCACCTACTAATATTATttttcacctactaaTA 52.9 1736 1736_1 TATTTTTCACCTACTAATATATTtttcacctactaaTA 54.9 1737 1737_1 TTTATTTTTCACCTACTAATATTTAtttttcacctactaaTA 52 1738 1738_1 TTTATTTTTCACCTACTAATTtatttttcacctaCTAA 51.2 1739 1739_1 TTTATTTTTCACCTACTATTTatttttcacctaCTA 19 1740 1740_1 CTCAACTTCTACTACTAATTCTCAacttctactactaaTT 19.7 1741 1741_1 TCTCAACTTCTACTACTAATTTCTCaacttctactactaaTT 25.8 1742 1742_1 CTCTCAACTTCTACTACTAATCTCtcaacttctactactAAT 43 1743 1743_1 CTCAACTTCTACTACTAATCTCAacttctactactaAT 20.1 1744 1744_1 TCTCAACTTCTACTACTAATTCTCaacttctactactaAT 22.8 1745 1745_1 TCTCTCAACTTCTACTACTAATCtctcaacttctactacTAA 58.4 1746 1746_1 CTCAACTTCTACTACTAACTcaacttctactaCTAA 47.3 1747 1747_1 TCTCAACTTCTACTACTAATCtcaacttctactaCTAA 56.3 1748 1748_1 CTCAACTTCTACTACTA CTCaacttctactaCTA10.7 1749 1749_1 TTCTCTCAACTTCTACTACTA TtctctcaacttctactaCTA 79.1 17501750_1 TCTCTCAACTTCTACTACTA TCtctcaacttctactacTA 61.2 1751 1751_1TCTCAACTTCTACTACTA TCtcaacttctactaCTA 66.8 1752 1752_1CTCTCAACTTCTACTACTA CtctcaacttctactACTA 61.7 1753 1753_1CTCTCAACTTCTACTACT CTCtcaacttctactaCT 37.9 1754 1754_1 TCTCAACTTCTACTACTTCtcaacttctacTACT 51.1 1755 1755_1 TCTCTCAACTTCTACTACTTCtctcaacttctactACT 44.2 1756 1756_1 TTTCTCTCAACTTCTACTACTTTtctctcaacttctactACT 65.7 1757 1757_1 TTCTCTCAACTTCTACTACTTTCtctcaacttctactaCT 33.5 1758 1758_1 TTTCTCTCAACTTCTACTACTTtctctcaacttctacTAC 67.9 1759 1759_1 CTCTCAACTTCTACTACCTCtcaacttctacTAC 34.1 1760 1760_1 TTCTCTCAACTTCTACTACTtctctcaacttctaCTAC 63.8 1761 1761_1 TTTTCTCTCAACTTCTACTACTTTTctctcaacttctactAC 20.6 1762 1762_1 TCTCTCAACTTCTACTACTCtctcaacttctacTAC 49.7 1763 1763_1 TTTCTCTCAACTTCTACTATTtctctcaacttctaCTA 60.2 1764 1764_1 TTTTCTCTCAACTTCTACTATtttctctcaacttctACTA 52.2 1765 1765_1 TTTTTCTCTCAACTTCTACTATTTttctctcaacttctacTA 40.2 1766 1766_1 TCTCTCAACTTCTACTATCtctcaacttctaCTA 47.5 1767 1767_1 TTCTCTCAACTTCTACTA TTCtctcaacttctacTA35.1 1768 1768_1 TTTCTCTCAACTTCTACT TTTCtctcaacttctaCT 28.6 1769 1769_1TTTTCTCTCAACTTCTACT TTTtctctcaacttctaCT 44.1 1770 1770_1CTTTTTCTCTCAACTTCTACT CtttttctctcaacttctaCT 99.8 1771 1771_1TTTTTCTCTCAACTTCTACT TTTttctctcaacttctaCT 43.7 1772 1772_1CTTTTTCTCTCAACTTCTAC CTTtttctctcaacttctAC 36.2 1773 1773_1ACTTTTTCTCTCAACTTCTAC ACTttttctctcaacttctAC 35.6 1774 1774_1TTTTCTCTCAACTTCTAC TtttctctcaacttCTAC 38.6 1775 1775_1TTTTTCTCTCAACTTCTAC TttttctctcaacttCTAC 42.1 1776 1776_1CTTTTTCTCTCAACTTCTA CTttttctctcaacttCTA 41.2 1777 1777_1TACTTTTTCTCTCAACTTCTA TactttttctctcaacttCTA 69.4 1778 1778_1ACTTTTTCTCTCAACTTCTA ActttttctctcaacttCTA 66.2 1779 1779_1TTTTTCTCTCAACTTCTA TttttctctcaactTCTA 35.5 1780 1780_1TACTTTTTCTCTCAACTTCT TActttttctctcaacttCT 65 1781 1781_1TTACTTTTTCTCTCAACTTCT TtactttttctctcaactTCT 62.1 1782 1782_1TTACTTTTTCTCTCAACTTC TTActttttctctcaactTC 38.9 1783 1783_1TACTTTTTCTCTCAACTTC TACtttttctctcaactTC 34 1784 1784_1ACTTTTTCTCTCAACTTC ActttttctctcaaCTTC 19.7 1785 1785_1TTACTTTTTCTCTCAACTT TTActttttctctcaaCTT 22 1786 1786_1TACTTTTTCTCTCAACTT TACtttttctctcaaCTT 22.3 1787 1787_1TTACTTTTTCTCTCAACT TTACtttttctctcaaCT 11.6 1788 1788_1GTTACTTTTTCTCTCAACT GTtactttttctctcAACT 43.2 1789 1789_1GTTACTTTTTCTCTCAAC GTtactttttctctCAAC 29 1790 1790_1 GTTACTTTTTCTCTCAAGTtactttttctcTCAA 5.53 1791 1791_1 AGTTACTTTTTCTCTCAA AGTtactttttctctCAA6.5 1792 1792_1 CTTTTACATTCCCATTAACA CTTTtacattcccattaaCA 24.5 17931793_1 CACTTTTACATTCCCATTAAC CACttttacattcccattaAC 25.3 1794 1794_1CTTTTACATTCCCATTAAC CTtttacattcccatTAAC 21.5 1795 1795_1ACTTTTACATTCCCATTAAC ACttttacattcccatTAAC 23 1796 1796_1ACTTTTACATTCCCATTAA ACttttacattcccaTTAA 30 1797 1797_1CTTTTACATTCCCATTAA CTtttacattcccaTTAA 27.4 1798 1798_1CACTTTTACATTCCCATTAA CActtttacattcccaTTAA 28 1798 1798_2CACTTTTACATTCCCATTAA CACttttacattcccatTAA 15.9 1799 1799_1TACACTTTTACATTCCCATTA TAcacttttacattcccatTA 52.2 1800 1800_1ACTTTTACATTCCCATTA ACTtttacattcccaTTA 13.1 1801 1801_1CACTTTTACATTCCCATTA CActtttacattcccATTA 15.7 1802 1802_1ACACTTTTACATTCCCATTA ACacttttacattcccaTTA 19.1 1802 1802_2ACACTTTTACATTCCCATTA ACActtttacattcccatTA 9.66 1803 1803_1CACTTTTACATTCCCATT CActtttacattccCATT 10.2 1804 1804_1TACACTTTTACATTCCCATT TACacttttacattcccaTT 10.3 1805 1805_1ACACTTTTACATTCCCATT ACACttttacattcccaTT 4.51 1805 1805_2ACACTTTTACATTCCCATT ACacttttacattccCATT 6.8 1806 1806_1TACACTTTTACATTCCCAT TACacttttacattccCAT 3.53 1806 1806_2TACACTTTTACATTCCCAT TACActtttacattcccAT 4.79 1807 1807_1TACACTTTTACATTCCCA TACacttttacattccCA 6.35 1808 1808_1GTACACTTTTACATTCCCA GtacacttttacattcCCA 3 1808 1808_2GTACACTTTTACATTCCCA GTacacttttacattccCA 16.3 1809 1809_1GTACACTTTTACATTCCC GTAcacttttacattcCC 4.33 1810 1810_1 TACACTTTTACATTCCCTACacttttacattcCC 3.26 1811 1811_1 TGTACACTTTTACATTCCCTGtacacttttacattcCC 12.3 1809 1809_2 GTACACTTTTACATTCCCGtacacttttacattCCC 2.49 1812 1812_1 TGTACACTTTTACATTCCTGtacacttttacatTCC 2.47 1813 1813_1 CTGTACACTTTTACATTCCTGtacacttttacaTTC 1.89 1814 1814_1 ATCTTATTTACATCTTCCATcttatttacatcTTCC 5.41 1815 1815_1 GAATCTTATTTACATCTTCGAatcttatttacatCTTC 25.8 1816 1816_1 GAATCTTATTTACATCTTGAatcttatttacaTCTT 19.1 1817 1817_1 TGAATCTTATTTACATCTTGAatcttatttacaTCT 41.3 1818 1818_1 ATTCAGCTTTTTCAATC ATTCagctttttcaaTC16.8 1819 1819_1 TTAATTTTCCCTTCACTCCT TtaattttcccttcactcCT 85.8 18201820_1 TTAATTTTCCCTTCACTCC TtaattttcccttcactCC 85.8 1821 1821_1TTAATTTTCCCTTCACTC TtaattttcccttcACTC 51 1822 1822_1 GTTAATTTTCCCTTCACTCGttaattttcccttcACTC 27.2 1823 1823_1 CAAAATTACTTCTTTTATCATCAaaattacttcttttaTCAT 86.7 1823 1823_2 CAAAATTACTTCTTTTATCATCAaaattacTtcttttaTCAT 51.5 1824 1824_1 CCAAAATTACTTCTTTTATCACCAaaattacttcttttaTCA 31.3 1824 1824_2 CCAAAATTACTTCTTTTATCACCaaaattacttcttttATCA 36 1825 1825_1 TCCAAAATTACTTCTTTTATCTCcaaaattacttctttTATC 40.9 1826 1826_1 TCCAAAATTACTTCTTTTATTCCaaaattacttctttTAT 50.2 1827 1827_1 CCAAAATTACTTCTTTTATCCAaaattacttctttTAT 70 1828 1828_1 TTCCAAAATTACTTCTTTTATTTCcaaaattacttctttTAT 64.9 1829 1829_1 TCCAAAATTACTTCTTTTATCCAaaattacttctttTA 36.9 1830 1830_1 TTCCAAAATTACTTCTTTTATTCCaaaattacttctttTA 52.2 1831 1831_1 GTTCCAAAATTACTTCTTTGTTCcaaaattacttctTT 54.8 1832 1832_1 GTTCCAAAATTACTTCTTGTtccaaaattactTCTT 12.5 1833 1833_1 TGTTCCAAAATTACTTCTTGTtccaaaattactTCT 20.1 1834 1834_1 ATGTTCCAAAATTACTTCATGTtccaaaattactTC 23.8 1835 1835_1 CATATTTTACTCTTTTTATTCATAttttactctttttaTT 90.6 1836 1836_1 CCATATTTTACTCTTTTTATCCATattttactctttttAT 35.4 1836 1836_2 CCATATTTTACTCTTTTTATCCAtattttactcttaTAT 60.8 1837 1837_1 CCCATATTTTACTCTTTTTATCccatattttactctttTTAT 75.8 1838 1838_1 CATATTTTACTCTTTTTATCATattttactcttttTAT 83.2 1839 1839_1 CCCATATTTTACTCTTTTTACCcatattttactcttttTA 81.1 1840 1840_1 CCATATTTTACTCTTTTTACCatattttactcttTTTA 24.7 1841 1841_1 ACCCATATTTTACTCTTTTTAAcccatattttactcttTTTA 59 1842 1842_1 CCATATTTTACTCTTTTTCCATattttactctttTT 21.6 1843 1843_1 CCCATATTTTACTCTTTTTCCcatattttactcttTTT 77.2 1844 1844_1 ACCCATATTTTACTCTTTTTACccatattttactctTTTT 97.4 1845 1845_1 TACCCATATTTTACTCTTTTTTAcccatattttactcttTTT 58.6 1846 1846_1 TACCCATATTTTACTCTTTTTACccatattttactctTTT 20.4 1847 1847_1 CCCATATTTTACTCTTTTCCCatattttactcttTT 93.2 1848 1848_1 ACCCATATTTTACTCTTTTACCcatattttactcttTT 21.8 1846 1846_2 TACCCATATTTTACTCTTTTTAcccatattttactcTTTT 22.5 1849 1849_1 TTACCCATATTTTACTCTTTTTTAcccatattttactcttTT 41.4 1850 1850_1 TACCCATATTTTACTCTTTTAcccatattttactCTTT 18.9 1851 1851_1 ACCCATATTTTACTCTTTACCcatattttactcTTT 13.4 1852 1852_1 TTACCCATATTTTACTCTTTTTacccatattttactCTTT 14.5 1853 1853_1 TTTACCCATATTTTACTCTTTTTTacccatattttactcTTT 22.2 1852 1852_2 TTACCCATATTTTACTCTTTTTACccatattttactctTT 16.7 1853 1853_2 TTTACCCATATTTTACTCTTTTTTAcccataactctTT 16 1854 1854_1 TTACCCATATTTTACTCTT TTAcccatattttactCTT14 1855 1855_1 TTTACCCATATTTTACTCTT TTtacccatattttacTCTT 14.9 18561856_1 ACCCATATTTTACTCTT ACCcatattttactCTT 8.02 1857 1857_1TACCCATATTTTACTCTT TACccatattttactCTT 16.7 1858 1858_1 TACCCATATTTTACTCTTACccatattttacTCT 22.3 1859 1859_1 TTACCCATATTTTACTCT TTACccatattttactCT15.2 1860 1860_1 TTTACCCATATTTTACTCT TTTAcccatattttactCT 11.8 18611861_1 TTACCCATATTTTACTC TTAcccatattttaCTC 24.4 1862 1862_1TTTACCCATATTTTACTC TTTacccatattttaCTC 14 1863 1863_1 GTTTACCCATATTTTACTCGTttacccatattttaCTC 12.2 1864 1864_1 GTTTACCCATATTTTACTGTttacccatatttTACT 24.9 1865 1865_1 TGTTTACCCATATTTTACTGTttacccatatttTAC 13.1 1866 1866_1 GTTTACCCATATTTTAC GTttacccatattTTAC13.2 1867 1867_1 TGTTTACCCATATTTTA TGTttacccatattTTA 6.69 1868 1868_1TTCTTGCTTCAACCATC TtcttgcttcaacCATC 13.6 1869 1869_1 GTTACCTCCCTTTATATGTtacctccctttatAT 60.9 1870 1870_1 GGTTACCTCCCTTTAT GgttacctccctTTAT 391871 1871_1 AGGTTACCTCCCTTTA AggttacctcccTTTA 35.4 1872 1872_1ATGTTCTCTATCTCTATA ATGttctctatctctATA 53.3 1873 1873_1 TATGTTCTCTATCTCTATAtgttctctatctCTA 73.4 1874 1874_1 AGATCAAACTAAAACCT AGAtcaaactaaaaCCT88.7 1875 1875_1 TGCCCAATTTCACCCAA TGcccaatttcacccAA 30.3 1876 1876_1TTTGCCCAATTTCACCC TttgcccaatttcacCC 53.3 1877 1877_1 TTTTGCCCAATTTCACCTTttgcccaatttcaCC 57.8 1878 1878_1 TGTATATCAACAATTCAT TGTatatcaacaattCAT20.8 1879 1879_1 ACATTTCTTTAAAATTTCCA ACatttctttaaaattTCCA 96.4 18791879_2 ACATTTCTTTAAAATTTCCA ACAtttctttaaaatttCCA 96.6 1880 1880_1CACATTTCTTTAAAATTTCCA CACAtttctttaaaatttcCA 95.5 1879 1879_3ACATTTCTTTAAAATTTCCA AcatttctttaaaattTCCA 98.1 1879 1879_4ACATTTCTTTAAAATTTCCA ACATttctttaaaatttcCA 98 1881 1881_1CCACATTTCTTTAAAATTTCC CcacatttctttaaaatTTCC 90 1882 1882_1CACATTTCTTTAAAATTTCC CAcatttctttaaaattTCC 94.8 1882 1882_2CACATTTCTTTAAAATTTCC CAcatttctttaaaatTTCC 89.1 1882 1882_3CACATTTCTTTAAAATTTCC CACAtttctttaaaatttCC 94.4 1883 1883_1ACATTTCTTTAAAATTTCC ACAtttctttaaaattTCC 91.9 1882 1882_4CACATTTCTTTAAAATTTCC CACatttctttaaaattTCC 92.4 1884 1884_1CCACATTTCTTTAAAATTTC CCACatttctttaaaattTC 98.3 1885 1885_1ACCACATTTCTTTAAAATTTC ACCAcatttctttaaaattTC 97.5 1884 1884_2CCACATTTCTTTAAAATTTC CCAcatttctttaaaattTC 102 1884 1884_3CCACATTTCTTTAAAATTTC CCacatttctttaaaaTTTC 94.9 1884 1884_4CCACATTTCTTTAAAATTTC CCAcatttctttaaaatTTC 87.2 1886 1886_1ACCACATTTCTTTAAAATTT ACCAcatttctttaaaatTT 94.8 1887 1887_1ACAAAACCACATTTCTTTAA ACAaaaccacatttcttTAA 97.4 1888 1888_1CTGTTTTCAAATCATTTC CTGTtttcaaatcattTC 15.8 1889 1889_1GAACCATTACTATTATCAA GAaccattactattaTCAA 27.3 1890 1890_1AGAACCATTACTATTATCA AGAaccattactattaTCA 19.8 1891 1891_1AGAACCATTACTATTATC AGaaccattactatTATC 17.9 1892 1892_1CTAGAACCATTACTATTA CTAGaaccattactatTA 35.3 1893 1893_1 TAGAACCATTACTATTATAGAaccattactatTA 13.2 1894 1894_1 CTAGAACCATTACTATT CTAGaaccattactaTT32.1 1895 1895_1 AGATTACCATCTTTCAAAA AGATtaccatctttcaaAA 59.5 18951895_2 AGATTACCATCTTTCAAAA AGAttaccatctttcaAAA 54.1 1896 1896_1AGATTACCATCTTTCAAA AGATtaccatctttcaAA 50.6 1896 1896_2AGATTACCATCTTTCAAA AGattaccatattCAAA 42.3 1897 1897_1 AGATTACCATCTTTCAAAGAttaccatctttCAA 32.4 1898 1898_1 AAGATTACCATCTTTCA AAGAttaccatattCA47.9 1899 1899_1 CATGCTCACACATTTTAA CATgctcacacatttTAA 60.5 1899 1899_2CATGCTCACACATTTTAA CAtgctcacacattTTAA 70.3 1899 1899_3CATGCTCACACATTTTAA CAtgctcacacatttTAA 69.8 1899 1899_4CATGCTCACACATTTTAA CATGctcacacattttAA 55.9 1900 1900_1 CTTAAGCTATCTAAACACTTAagctatctaaaCA 82.6 1901 1901_1 TGAACAATTCAACATTCA TGAacaattcaacatTCA67.7 1902 1902_1 GATCAAAAAACTTTCCCT GAtcaaaaaactttCCCT 76.1 1903 1903_1AGATCAAAAAACTTTCCCT AGatcaaaaaactttCCCT 70.4 1904 1904_1AGATCAAAAAACTTTCCC AGAtcaaaaaactaCCC 73.6 1905 1905_1 TCCTAGATCAAAAAACTTCCTagatcaaaaaaCT 69.9 1906 1906_1 ATTTTTTCTTCTCTTTTCA ATTTtttcttcttttCA8.98 1907 1907_1 TATTTTTTCTTCTCTTTTCA TATtttttcttctcttttCA 63.8 19081908_1 ATATTTTTTCTTCTCTTTTC ATattttttcttctctTTTC 16.1 1909 1909_1TCTGCTTTAAAAACTCTC TCtgctttaaaaacTCTC 34.3 1910 1910_1 CTCTGCTTTAAAAACTCCTCtgctttaaaaaCTC 51.6 1911 1911_1 ACTACACAAACACATTCAAACtacacaaacacatTCAA 37.6 1912 1912_1 CAAACTACACAAACACATTCACAaactacacaaacacaTTCA 41.2 1913 1913_1 ACAAACTACACAAACACATTCACAaactacacaaacacaTTC 63.1 1914 1914_1 CAACAAACTACACAAACACATCAAcaaactacacaaacaCAT 86.1 1915 1915_1 CACAACAAACTACACAAACACCACaacaaactacacaaaCAC 62.1 1916 1916_1 TCACAACAAACTACACAAACATCACaacaaactacacaaaCA 48.6 1917 1917_1 TTCACAACAAACTACACAAACTTCAcaacaaactacacaaAC 58.8 1918 1918_1 ATTTCACAACAAACTACACAAATTtcacaacaaactacaCAA 76.8 1919 1919_1 CAATTTCACAACAAACTACACCAAtttcacaacaaactaCAC 70.7 1920 1920_1 TGTAACAATTTCACAACAATGTaacaatttcacaaCAA 59.5 1921 1921_1 TGTAACAATTTCACAACATGTAacaatttcacaaCA 28.7 1922 1922_1 TTAAGCCAACCCCACCA TtaagccaaccccacCA83.1 1923 1923_1 TTTAAGCCAACCCCACC TttaagccaaccccACC 69.2 1924 1924_1ATTTAAGCCAACCCCAC AtttaagccaaccCCAC 60.6 1925 1925_1 CCAGTAATACAAATTATACCAGtaatacaaattaTA 69.5 1926 1926_1 CCCAGTAATACAAATTA CCCAgtaatacaaatTA55.9 1927 1927_1 TCCCAGTAATACAAATT TCCCagtaatacaaaTT 64.9 1928 1928_1ATCCCAGTAATACAAAT ATCCcagtaatacaaAT 65.9 1929 1929_1 CTACTAGCATCACCACTCtactagcatcacCACT 19.8 1930 1930_1 TTCTACTAGCATCACC TtctactagcatCACC21.8 1931 1931_1 CTTCTACTAGCATCAC CTtctactagcaTCAC 33.2 1932 1932_1TAAATTACTCATTAAATCCAT TAaattactcattaaatCCAT 77.8 1933 1933_1ATAAATTACTCATTAAATCCA ATaaattactcattaaaTCCA 52.4 1934 1934_1TAAATTACTCATTAAATCCA TAaattactcattaaaTCCA 51.6 1935 1935_1CATAAATTACTCATTAAATCC CATaaattactcattaaaTCC 58.5 1935 1935_2CATAAATTACTCATTAAATCC CATaaattacTcattaaaTCC 22.3 1936 1936_1GATTTATTTTTCTACTTA GAtttatwtctaCTTA 66 1937 1937_1 ATACAACAAACAATTCACTTTATacaacaaacaattcaCTTT 53.2 1937 1937_2 ATACAACAAACAATTCACTTTATACaacaaacaattcactTT 48.1 1938 1938_1 CGATACAACAAACAATTCACGATacaacaaacaattCA 23 1939 1939_1 GAACATCCACACTAACAACAGAACatccacactaacaaCA 43.6 1940 1940_1 ACATCCACACTAACAACAACAtccacactaacaACA 65 1939 1939_2 GAACATCCACACTAACAACAGAAcatccacactaacaACA 52 1939 1939_3 GAACATCCACACTAACAACAGAacatccacactaacAACA 58.1 1941 1941_1 GAACATCCACACTAACAACGAACatccacactaacaAC 51.3 1941 1941_2 GAACATCCACACTAACAACGAacatccacactaaCAAC 63.3 1942 1942_1 TGAACATCCACACTAACAATGAacatccacactaaCAA 57.8 1943 1943_1 TTGAACATCCACACTAACATTGAacatccacactaaCA 60.3 1944 1944_1 TGAACATCCACACTAACATGAAcatccacactaaCA 42.6 1945 1945_1 CATTGAACATCCACACTACATtgaacatccacaCTA 59.4 1946 1946_1 ATTGAACATCCACACTA ATTgaacatccacaCTA50 1947 1947_1 CATTGAACATCCACACT CAttgaacatccaCACT 43 1948 1948_1ACTCATTGAACATCCAC ACtcattgaacatCCAC 46.8 1949 1949_1TATCTTTATTTAATAATCTT TATCtttatttaataatcTT 93.4 1949 1949_2TATCTTTATTTAATAATCTT TAtctttatttaataaTCTT 96.9 1950 1950_1TCTCAAGCTTCACTCTA TCtcaagcttcactcTA 78.6 1951 1951_1 GACAATATATTCCTCAATCGACAatatattcctcaaTC 73 1952 1952_1 GACAATATATTCCTCAAT GACAatatattcctcaAT82 1952 1952_2 GACAATATATTCCTCAAT GAcaatatattcctCAAT 76.8 1953 1953_1TCCTGTAACAATTATAC TCCtgtaacaattaTAC 95.4 1954 1954_1 ACCCAGAATAAAAACCACACccagaataaaaaCCAC 95.5 1955 1955_1 TTCCACTTTCTTACTCCCTtccactttcttactcCC 96.6 1956 1956_1 TTCCACTTTCTTACTCC TtccactttcttacTCC86.3 1957 1957_1 TTTCCACTTTCTTACTCC TttccactttcttacTCC 89.2 1958 1958_1TTTCCACTTTCTTACTC TTTCcactttcttacTC 89.2 1959 1959_1 ATCCCTTTACCACTTTTATCcctttaccactTTT 101 1960 1960_1 CATCCCTTTACCACTTTT CAtccctttaccactTTT98 1961 1961_1 TCATCCCTTTACCACTTT TCatccctttaccactTT 101 1962 1962_1TCATCCCTTTACCACTT TCAtccctttaccacTT 96.9 1963 1963_1 CTCATCCCTTTACCACTTCtcatccctttaccacTT 97.7 1964 1964_1 GTCTACATCTAACCCC GtctacatctaacCCC 971965 1965_1 AGTCTACATCTAACCCC AGtctacatctaaccCC 99.6 1966 1966_1CAGTCTACATCTAACCCC CagtctacatctaaccCC 97.4 1967 1967_1 CAGTCTACATCTAACCCCagtctacatctaaCCC 99.5 1968 1968_1 TCAGTCTACATCTAACCC TCagtctacatctaacCC98.9 1969 1969_1 AGTCTACATCTAACCC AGTctacatctaacCC 98.2 1970 1970_1TCAGTCTACATCTAACC TCagtctacatctAACC 98.3 1971 1971_1 TTCAGTCTACATCTAACCTTCagtctacatctaaCC 98 1972 1972_1 TTCAGTCTACATCTAAC TTCAgtctacatctaAC98.7 1973 1973_1 TTTCAGTCTACATCTAA TTtcagtctacatCTAA 90.1 1974 1974_1AGTTTTAACCACACCTCCT AgttttaaccacacctcCT 102 1975 1975_1GTTTTAACCACACCTCC GTTttaaccacacctCC 93.7 1976 1976_1 AGTTTTAACCACACCTCCAgttttaaccacaccTCC 95 1977 1977_1 AGTTTTAACCACACCTC AGttttaaccacacCTC88.7 1978 1978_1 GAGTTTTAACCACACC GAGMtaaccacACC 94.7 1979 1979_1CAGATCTTCTCTTTATTT CAGatcttctctttaTTT 96.3 1980 1980_1TGTTTTCAACAAAACATCA TGTtttcaacaaaacaTCA 89.9 1981 1981_1TGTTTTCAACAAAACATC TGttacaacaaaaCATC 97.5 1982 1982_1 CTGTTTTCAACAAAACATCTGttttcaacaaaaCAT 102 1983 1983_1 TCTGTTTTCAACAAAACA TCTGttacaacaaaaCA98 1984 1984_1 ATCTTTCTAAAACTTACC ATCTttctaaaacttaCC 96.3 1985 1985_1CAGAATCTTTCTAAAACT CAGAatctttctaaaaCT 91.7 1986 1986_1 CTACAGAATCTTTCTAACTacagaatctttCTAA 97.6 1986 1986_2 CTACAGAATCTTTCTAA CTAcagaatctttcTAA95.6 1987 1987_1 ATTTCCCTTTATTTCCCTT AtttccctttatttccCTT 92 1988 1988_1GTATTTCCCTTTATTTCC GtatttccctttattTCC 99.5

In the oligonucleotide compound column, capital letters representbeta-D-oxy LNA nucleosides, LNA cytosines are 5-methyl cytosine, lowercase letters are DNA nucleosides, and all internucleoside linkages arephosphorothioate. ^(m)c represent 5-methyl cytosine DNA nucleosides(used in compounds 1490_1 and 1491_1).

Example 4 Materials and Methods:

The screening assay described in Example 2 was performed using a seriesof further oligonucleotide targeting human ATXN3 pre-mRNA using theqpCR: (ATXN3 exon 8-9(1) PrimeTime® XL qPCR Assay (IDT).

qPCR probe and primers set 2: (SEQ ID NO: 1134)Probe: 5′-/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCT AAGT/ 31ABkFQ/-3′(SEQ ID NO: 1135) Primer 1: 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′(SEQ ID NO: 1136) Primer 2: 5′-CATGGAAGATGAGGAAGCAGAT-3′

Results:

TABLE 6 % of ATXN3 Oligonucleotide Oligonucleotide mRNA SEQID CMPIDBase Sequence compound remaining 1110 1110_2 ACATCATTTATCACTACCACACatcatttatcactacCAC 44 1102 1102_2 TATCTCAAACTATCCCCATatctcaaactatccCCA 74 1104 1104_2 TCCCCTAAATAATTTAATCATCCcctaaataatttaaTCA 78 1116 1116_2 TCTTCATTATACCATCAAATTCTTcattataccatcaaAT 12 1121 1121_2 CTCTCAACTTCTACTACTAACtctcaacttctactaCTAA 68 1114 1114_2 TGATTCTTATACTTACTATGATtcttatacttacTA 64 1120 1120_2 CATCACAAAATAACCTATCACATCacaaaataacctatCA 38 1100 1100_2 CCCCATTCAAATATTTATTCCCcattcaaatatttATT 79 1112 1112_2 TCAGATCCTAAAATCACT TCAGatcctaaaatcaCT65 1123 1123_2 CCAAAATTACTTCTTTTATC CCaaaattacttctttTATC 37 1117 1117_2GTTTCATATTTTTAATCC GTftcatatttttaATCC 10 1099 1099_2 CCAAAAGAAACCAAACCCCCaaaagaaaccaaACCC 88 1109 1109_2 TGAAACCATTACTACAACCTGAaaccattactacaACC 22 1113 1113_2 CTATACCTAAAACAATCTACTatacctaaaacaaTCTA 86 1119 1119_2 CAAATATTCACAAATCCTACaaatattcacaaatCCTA 78 1125 1125_2 ACAATATATTCCTCAATCAACaatatattcctcaATCA 74 1127 1127_2 CATCCCTTTACCACTTT CatccctttaccaCTTT97 1118 1118_2 TAATATCCTCATTACCCATT TaatatcctcattaccCATT 97 1103 1103_2TCTATTCCTTAACCCAAC TCtattccttaaccCAAC 81 1122 1122_2 AATCTTATTTACATCTTCCAATCttatttacatcttCC 11 1126 1126 2 CCTGTAACAATTATACA CCTGtaacaattataCA93 1122 1122_3 AATCTTATTTACATCTTCC AatcttatttacaTCtTCC 54 1122 1122_4AATCTTATTTACATCTTCC AAtcTtatttacAtCttCC 17 1122 1122_5AATCTTATTTACATCTTCC AAtcttatttacAtCttCC 21 1122 1122_6AATCTTATTTACATCTTCC AatctTatttacaTCttCC 12 1122 1122_7AATCTTATTTACATCTTCC AatcttatttacAtCttCC 28 1122 1122_8AATCTTATTTACATCTTCC AAtcttatttacAtcTTCC 28 1122 1122_9AATCTTATTTACATCTTCC AAtcTtatttacAtctTCC 11 1122 1122_10AATCTTATTTACATCTTCC AatctTatttacAtctTCC 9 1122 1122_11AATCTTATTTACATCTTCC AatcTtatttacatcTTCC 10 1122 1122_12AATCTTATTTACATCTTCC AATcTtatttacAtcTtCC 10 1122 1122_13AATCTTATTTACATCTTCC AatCTtatttacAtcttCC 10 1122 1122_14AATCTTATTTACATCTTCC AatCttatttacatctTCC 7 1122 1122_15AATCTTATTTACATCTTCC AatcttatttacaTCttCC 32 1122 1122_16AATCTTATTTACATCTTCC AatCttatttacatcTTCC 4 1122 1122_17AATCTTATTTACATCTTCC AAtCttatttacatcTtCC 5 1122 1122_18AATCTTATTTACATCTTCC AaTcTtatttacaTcTtCC 9 1122 1122_19AATCTTATTTACATCTTCC AatcTTatttacatcTtCC 5 1122 1122_20AATCTTATTTACATCTTCC AatcTtatttacatCttCC 13 1122 1122_21AATCTTATTTACATCTTCC AAtcttatttacatCttCC 23 1122 1122_22AATCTTATTTACATCTTCC AatctTatttacatCttCC 8 1122 1122_23AATCTTATTTACATCTTCC AatcTTatttacatCttCC 4 1122 1122_24AATCTTATTTACATCTTCC AatctTatttacatcTTCC 8 1122 1122_25AATCTTATTTACATCTTCC AATcTTatttacatcTtCC 5 1122 1122_26AATCTTATTTACATCTTCC AAtctTatttacatcTtCC 12 1122 1122_27AATCTTATTTACATCTTCC AaTCTtatttacatcTtCC 3 1122 1122_28AATCTTATTTACATCTTCC AaTcTTatttacatcTtCC 3 1122 1122_29AATCTTATTTACATCTTCC AatCTTatttacatcTtCC 3 1122 1122_30AATCTTATTTACATCTTCC AAtcTTatttacatctTCC 5 1122 1122_31AATCTTATTTACATCTTCC AAtcTtatttacatctTCC 12 1122 1122_32AATCTTATTTACATCTTCC AAtcttatttacatctTCC 33 1122 1122_33AATCTTATTTACATCTTCC AatCtTatttacatctTCC 3 1122 1122_34AATCTTATTTACATCTTCC AatcTTatttacatctTCC 6 1122 1122_35AATCTTATTTACATCTTCC AatcTtatttacatctTCC 16 1122 1122_36AATCTTATTTACATCTTCC AATCtTatttacatcttCC 8 1122 1122_37AATCTTATTTACATCTTCC AAtCTTatttacatcttCC 5 1122 1122_38AATCTTATTTACATCTTCC AAtCttatttacatcttCC 16 1122 1122_39AATCTTATTTACATCTTCC AaTCTtatttacatcttCC 7 1122 1122_40AATCTTATTTACATCTTCC AaTCtTatttacatcttCC 5 1122 1122_41AATCTTATTTACATCTTCC AatCTTatttacatcttCC 5 1122 1122_42AATCTTATTTACATCTTCC AatCTtatttacatcttCC 13 1122 1122_43AATCTTATTTACATCTTCC AatcTTatttacatcttCC 17 1109 1109_3TGAAACCATTACTACAACC TgaaaccattacTAcaaCC 58 1109 1109_4TGAAACCATTACTACAACC TgaaaccattacTAcAaCC 20 1109 1109_5TGAAACCATTACTACAACC TgaAAccattacTacAaCC 23 1109 1109_6TGAAACCATTACTACAACC TgAaAccattactAcaaCC 50 1109 1109_7TGAAACCATTACTACAACC TgAaaCcattactAcaaCC 46 1109 1109_8TGAAACCATTACTACAACC TgaAAccattacTacaaCC 48 1109 1109_9TGAAACCATTACTACAACC TgaaaccattactaCAaCC 25 1109 1109_10TGAAACCATTACTACAACC TgaaAccattacTaCaACC 24 1109 1109_11TGAAACCATTACTACAACC TGaaAccattactaCaaCC 36 1109 1109_12TGAAACCATTACTACAACC TgAAAccattactaCaaCC 20 1109 1109_13TGAAACCATTACTACAACC TgAAaCcattactaCaaCC 26 1109 1109_14TGAAACCATTACTACAACC TgAaaccattactaCaaCC 27 1109 1109_15TGAAACCATTACTACAACC TGaAaccattacTacAaCC 14 1109 1109_16TGAAACCATTACTACAACC TgAaaCcattactacAACC 12 1109 1109_17TGAAACCATTACTACAACC TgaaaCcattacTacAaCC 36 1109 1109_18TGAAACCATTACTACAACC TgaaaCcattacTacaaCC 62 1109 1109_19TGAAACCATTACTACAACC TGaaAccattactacaaCC 47 1109 1109_20TGAAACCATTACTACAACC TgaAaccattactaCAaCC 19 1109 1109_21TGAAACCATTACTACAACC TgaAaccattactACaACC 16 1109 1109_22TGAAACCATTACTACAACC TgAAaccattactACaACC 9 1109 1109_23TGAAACCATTACTACAACC TgAaAccattactAcaACC 29 1109 1109_24TGAAACCATTACTACAACC TgaaaCcattactAcaACC 41 1109 1109_25TGAAACCATTACTACAACC TgaAACcattactAcaaCC 34 1109 1109_26TGAAACCATTACTACAACC TgaAaCcattactaCaaCC 28 1109 1109_27TGAAACCATTACTACAACC TGaAaCcattactacAACC 10 1109 1109_28TGAAACCATTACTACAACC TgAAaCcattactAcAACC 52 1109 1109_29TGAAACCATTACTACAACC TGaAAccattactacaACC 16 1109 1109_30TGAAACCATTACTACAACC TGAaaccattactacaaCC 36 1109 1109_31TGAAACCATTACTACAACC TgaaaCcattactaCaACC 21 1109 1109_32TGAAACCATTACTACAACC TgAAAccattactacAACC 9 1109 1109_33TGAAACCATTACTACAACC TgAaaCcattactacAaCC 14 1109 1109_34TGAAACCATTACTACAACC TGaaaccattactacaACC 43 1109 1109_35TGAAACCATTACTACAACC TgAAaCcattactacaACC 15 1109 1109_36TGAAACCATTACTACAACC TgaAACcattactacaaCC 15 1109 1109_37TGAAACCATTACTACAACC TGaAaCcattactacaaCC 16 1109 1109_38TGAAACCATTACTACAACC TGaaaCcattactacaaCC 38 1109 1109_39TGAAACCATTACTACAACC TgAAACcattactacaaCC 14 1109 1109_40TGAAACCATTACTACAACC TgAAaCcattactacaaCC 16 1109 1109_41TGAAACCATTACTACAACC TgaAaCcattactacaaCC 28 1109 1109_42TGAAACCATTACTACAACC TgaaACcattactacaaCC 28 1122 1122_44AATCTTATTTACATCTTCC AatcttatttacaTCTtCC 65 1122 1122_45AATCTTATTTACATCTTCC AatcTtatttacAtCttCC 38 1122 1122_46AATCTTATTTACATCTTCC AatcTtatttacaTcTTCC 34 1122 1122_47AATCTTATTTACATCTTCC AAtCttatttacAtcTtCC 10 1122 1122_48AATCTTATTTACATCTTCC AAtcTtatttacATcTtCC 35 1122 1122_49AATCTTATTTACATCTTCC AatCttatttacAtcTtCC 10 1122 1122_50AATCTTATTTACATCTTCC AAtCttatttacAtcttCC 11 1122 1122_51AATCTTATTTACATCTTCC AAtctTatttacatCTtCC 9 1122 1122_52AATCTTATTTACATCTTCC AatcTTatttacAtcTtCC 12 1122 1122_53AATCTTATTTACATCTTCC AatctTatttacatCTtCC 8 1122 1122_54AATCTTATTTACATCTTCC AaTcTtatttacatcTTCC 4 1122 1122_55AATCTTATTTACATCTTCC AAtcttatttacAtcTtCC 27 1122 1122_56AATCTTATTTACATCTTCC AAtCtTatttacAtcttCC 5 1122 1122_57AATCTTATTTACATCTTCC AAtcTTatttacatcttCC 14 1122 1122_58AATCTTATTTACATCTTCC AaTCttatttacatcttCC 13 1122 1122_59AATCTTATTTACATCTTCC AATcttatttacatCttCC 6 1122 1122_60AATCTTATTTACATCTTCC AAtcTtatttacatCttCC 10 1122 1122_61AATCTTATTTACATCTTCC AAtcTTatttacatcTtCC 6 1122 1122_62AATCTTATTTACATCTTCC AatCtTatttacatcTtCC 3 1122 1122_63AATCTTATTTACATCTTCC AATCttatttacaTcttCC 5 1122 1122_64AATCTTATTTACATCTTCC AatCttatttacatcTtCC 7 1122 1122_65AATCTTATTTACATCTTCC AatCttatttacatcttCC 32 1122 1122_66AATCTTATTTACATCTTCC AatcttatttacatcTTCC 19 1122 1122_67AATCTTATTTACATCTTCC AATCttatttacatcTtCC 3 1122 1122_68AATCTTATTTACATCTTCC AATcTtatttacatcTtCC 4 1122 1122_69AATCTTATTTACATCTTCC AAtCTtatttacatcTtCC 3 1122 1122_70AATCTTATTTACATCTTCC AAtCtTatttacatcTtCC 3 1122 1122_71AATCTTATTTACATCTTCC AAtcTtatttacatcTtCC 13 1122 1122_72AATCTTATTTACATCTTCC AaTCttatttacatcTtCC 5 1122 1122_73AATCTTATTTACATCTTCC AatCTtatttacatcTtCC 5 1122 1122_74AATCTTATTTACATCTTCC AatctTatttacatcTtCC 10 1122 1122_75AATCTTATTTACATCTTCC AAtCTtatttacatctTCC 3 1122 1122_76AATCTTATTTACATCTTCC AAtCttatttacatctTCC 5 1122 1122_77AATCTTATTTACATCTTCC AaTCttatttacatctTCC 5 1122 1122_78AATCTTATTTACATCTTCC AatCTtatttacatctTCC 4 1122 1122_79AATCTTATTTACATCTTCC AAtCTtatttacatcttCC 7 1122 1122_80AATCTTATTTACATCTTCC AAtCtTatttacatcttCC 5 1122 1122_81AATCTTATTTACATCTTCC AatCtTatttacatcttCC 8 1109 1109_43TGAAACCATTACTACAACC TgAAaccattacTAcAaCC 18 1109 1109_44TGAAACCATTACTACAACC TgAaAccattacTacAaCC 27 1109 1109_45TGAAACCATTACTACAACC TgaAaCcattacTacAaCC 65 1109 1109_46TGAAACCATTACTACAACC TgAaaccattacTacaACC 25 1109 1109_47TGAAACCATTACTACAACC TgaAaccattacTacaACC 35 1109 1109_48TGAAACCATTACTACAACC TgaaAccattacTacaACC 48 1109 1109_49TGAAACCATTACTACAACC TgaAaCcattacTacaaCC 44 1109 1109_50TGAAACCATTACTACAACC TgaAaccattacTaCaaCC 34 1109 1109_51TGAAACCATTACTACAACC TGaaaccattacTacaACC 29 1109 1109_52TGAAACCATTACTACAACC TgAAaccattacTacaACC 23 1109 1109_53TGAAACCATTACTACAACC TgaaaCcattacTaCaaCC 39 1109 1109_54TGAAACCATTACTACAACC TGaaaccattactaCaaCC 33 1109 1109_55TGAAACCATTACTACAACC TgAaAccattactaCaaCC 29 1109 1109_56TGAAACCATTACTACAACC TGaaAccattactacAACC 16 1109 1109_57TGAAACCATTACTACAACC TGaaAccattactacAaCC 18 1109 1109_58TGAAACCATTACTACAACC TgAaACcattactacaaCC 12 1109 1109_59TGAAACCATTACTACAACC TgAaaccattactaCAaCC 13 1109 1109_60TGAAACCATTACTACAACC TgaaAccattactACaaCC 36 1109 1109_61TGAAACCATTACTACAACC TGaaaccattactAcaACC 34 1109 1109_62TGAAACCATTACTACAACC TgAaaCcattactACaaCC 43 1109 1109_63TGAAACCATTACTACAACC TGaAAccattactaCaaCC 19 1109 1109_64TGAAACCATTACTACAACC TGaaaCcattactACaaCC 29 1109 1109_65TGAAACCATTACTACAACC TGaAaccattactAcaaCC 40 1109 1109_66TGAAACCATTACTACAACC TgaAAccattactAcAACC 14 1109 1109_67TGAAACCATTACTACAACC TGaAaccattactAcAaCC 14 1109 1109_68TGAAACCATTACTACAACC TGaaaCcattactAcAaCC 27 1109 1109_69TGAAACCATTACTACAACC TgAaaCcattactAcAACC 31 1109 1109_70TGAAACCATTACTACAACC TgAaAccattactAcAaCC 24 1109 1109_71TGAAACCATTACTACAACC TgaaACcattactacAACC 10 1109 1109_72TGAAACCATTACTACAACC TGAaaccattactacAaCC 11 1109 1109_73TGAAACCATTACTACAACC TgaAACcattactAcAaCC 34 1109 1109_74TGAAACCATTACTACAACC TGaAaCcattactacaACC 15 1109 1109_75TGAAACCATTACTACAACC TGaaACcattactacaaCC 14 1109 1109_76TGAAACCATTACTACAACC TGaAaccattactaCaaCC 22 1109 1109_77TGAAACCATTACTACAACC TgaAAccattactaCaaCC 30 1109 1109_78TGAAACCATTACTACAACC TgaaAccattactaCaaCC 50 1109 1109_79TGAAACCATTACTACAACC TgaAACcattactacAaCC 9 1109 1109_80TGAAACCATTACTACAACC TGaAaccattactacaaCC 31 1109 1109_81TGAAACCATTACTACAACC TgAaaCcattactacaaCC 31In the oligonucleotide compound column, capital letters representbeta-D-oxy LNA nucleosides, LNA cytosines are 5-methyl cytosine, lowercase letters are DNA nucleosides, and all internucleoside linkages arephosphorothioate.

Example 5: Testing in vitro efficacy of LNA oligonucleotides in iCell®GlutaNeurons at 25 μM Materials and Methods:

An oligonucleotide screen was performed in a human cell line usingselected LNA oligonucleotides from the previous examples.

The iCell® GlutaNeurons derived from human induced pluripotent stem cellwere purchased from the vendor listed in Table 2, and were maintained asrecommended by the supplier in a humidified incubator at 37° C. with 5%CO₂. For the screening assays, cells were seeded in 96 multi well platesin media recommended by the supplier (see Table 2 in the Materials andMethods section). The number of cells/well was optimized (Table 2).

Cells were grown for 7 days before addition of the oligonucleotide inconcentration of 25 μM (dissolved in medium). 4 days after addition ofthe oligonucleotide, the cells were harvested.

RNA extraction and qPCR was performed as described for “Example 1”

Primer assays for ATXN3 and house keeping gene were:

ATXN3 primer assay (Assay ID: N/A, Item Name: Hs.PT.58.39355049):(SEQ ID NO: 1128) Forward primer: GTTTCTAAAGACATGGTCACAGC(SEQ ID NO: 1129) Reverse: CTATCAGGACAGAGTTCACATCC (SEQ ID NO: 1030)Probe: 56-FAM/AAAGGCCAG/ZEN/CCACCAGTTCAGG/3IABkFQ/TBP primer assay (Assay ID: N/A, Item name: Hs.PT.58v.39858774(SEQ ID NO: 1131) Probe: 5′-/5HEX/TGA TCT TTG/ZEN/CAG TGA CCCAGC ATC A/3IABkFQ/-3′ (SEQ ID NO: 1132)Primer 1: 5′-GCT GTT TAA CTT CGC TTC CG-3′ (SEQ ID NO: 1133)Primer 2: 5′-CAG CAA CTT CCT CAA TTC CTT G-3′

Results:

The relative ATXN3 mRNA expression levels were determined as % ofcontrol (medium-treated cells) i.e. the lower the value the larger theinhibition.

The compounds tested and the target knock-down data is presented inTable 7.

Example 6: Determination of EC50 values of LNA gapmers targeting ATXN3Materials and Methods:

Values for EC50 (concentration at which half effect on target knockdownis observed) was determined for the cell lines SK-N-AS, A431 and iPSCs(iCell® GlutaNeurons). The following oligoconcentrations were used:

-   -   SK-N-AS: 50 μM—half log dilution (3.16 fold)—8 steps including        blank control    -   A431: 50 μM—half log dilution (3.16 fold)—8 steps including        blank control    -   iPCS: 10 μM—10 fold dilution—8 steps including blank control

The cells were treated with oligo, lysed and analysed as indicated inprevious examples.

Results:

The compounds tested and their EC50 values is shown in table 7.

Example 7: In vitro toxicity evaluation Materials and Methods:

The criterion for selection of oligonucleotides assessed in the varioussafety assays is based on the magnitude and frequency of signalsobtained. Safety assays used were: Caspase activation, hepatotoxicity,nephrotoxicity toxicity and immunotoxicity assays. The signals obtainedin the individual in vitro safety assays result in a score (0-safe, 0.5borderline toxicity, 1-mild toxicity, 2-medium toxicity and 3-severetoxicity) and are summarized into a cumulative score for each sequence(See table 7), providing an objective ranking of compounds. As reportedin the references provided, the signal strength is a measure of risk forin vivo toxicity based on validation of the assays using in vivorelevant reference molecules

In vitro toxicity assays were performed as described in the followingreferences: Caspase activation assay: Dieckmann et al., MolecularTherapy: Nucleic Acids Vol. 10 Mar. 2018, pp 45-54.

Hepatotoxicity toxicity assay: Sewing et al., Methods in MolecularBiology Oligonucleotide-Based Therapies MIMB, volume 2036, pp 249-2592019, Sewing et al., PLOS ONE DOI:10.1371/journal.pone.0159431 Jul. 21,2016.

Nephrotoxicity toxicity assay: Moisan et al., Mol Ther Nucleic Acids.2017 Mar. 17; 6:89-105. doi: 10.1016/j.omtn.2016.11.006. Epub 2016 Dec.10.

Immunotoxicity: Sewing et al., PLoS One. 2017 Nov. 6;12(11):e0187574.doi: 10.1371/journal.pone.0187574. eCollection 2017.

As part of the screening cascade 1170 compounds were evaluated in thecell lines SK-N-AS and A431 where compound efficacy was evaluated(Tables 4-6). Of these, 50 of the most effective compounds wereevaluated for caspase activation of which 18 underwent furtherevaluation in the descried in the three other in vitro tox assays(cumulative score is shown in Table 7).

Results:

Conclusively, 8 compounds were identified as being highly effective andpotent in vitro, and with a low or absent toxicity in the 4 in vitroassays these compounds were therefore selected for evaluated intransgenic mice expressing human ATNX3 pre-mRNA: Compounds #1856_1,1813_1, 1812_1, 1809_2, 1607_1, 1122_62, 1122_67 and 1122_33.

TABLE 7 Data obtained from examples 5, 6 & 7 HiPCS, Maximal TotalSK-N-AS A-431 HiPSC efficacy at 25 μM tox EC50 EC50 EC50 (% remainingCMPID score (μM) (μM) (μM) ATXN3 transcript) 1856_1 1.5 0.53 0.22 0.232.87 1806_2 2   0.35 0.19 0.03 0.91 1888_1 — 0.72 0.54 — 1813_1 2   0.240.08 0.04 1.85 1640_1 — 1.50 0.19 — 1812_1 1.5 0.20 0.09 0.09 0.591117_2 — 0.73 0.57 — 1810_1 — 0.36 0.14 — 1809_2  1.25 0.22 0.09 0.051.44 1489_1 — 1.16 0.30 — 1867_1 — 0.54 0.50 — 1893_1 — 0.95 0.34 0.41 41906_1 — 0.36 0.57 0.04 2.55 1214_1 — 1.05 0.38 — 1213_1 — 1.01 0.38 —1423_1 — 0.75 0.23 0.03 3.58 1790_1 — 0.42 0.47 — 1605_1 — 0.47 0.17 —1607_1 2.5 0.32 0.25 0.08 4.46 1805_1 — 0.75 0.23 — 1806_1 — 0.45 0.200.04 1.3 1809_1 3   0.24 0.20 0.02 1.81 1808_1 2   0.26 0.22 0.06 1.41625_1 0.5 0.94 0.25 0.66 7.16 1122_54 — 0.62 0.15 — 1122_16 — 0.30 0.15— 1122_17 — 0.33 0.17 0.11 1.07 1122_62 0.5 0.21 0.10 0.03 3.53 1122_19— 0.28 0.24 — 1122_23 — 0.54 0.18 0.05 0.59 1122_67 0   0.29 0.10 0.010.52 1122_68 — 0.28 0.13 0.01 1122_69 — 0.27 0.12 — 1122_70 — 0.20 0.10— 1122_27 1   0.23 0.12 0.03 0.55 1122_72 0.5 0.25 0.15 0.06 2.281122_28 1   0.20 0.12 0.01 0.37 1122_29 — 0.19 0.09 0.02 1.6 1122_73 —0.29 0.18 0.04 1.59 1122_75 1   0.44 0.12 0.03 2 1122_76 — 0.33 0.19 —1122_77 1   0.30 0.20 0.04 1.97 1122_78 — 0.29 0.18 0.02 1.91 1122_33 1.25 0.18 0.10 0.02 1.84 1122_37 — 0.25 0.13 0.03 0.89 1122_80 — 0.330.17 — 1122_41 — 0.24 0.16 0.01 0.47 1109_22 — 0.90 0.23 0.11 8.411109_32 0   0.75 0.17 0.09 3.49 1109_79 — 1.48 0.20 —

Example 8: In vivo transgenic mouse study Materials and Methods:

Animal Care

In vivo activity and tolerability of the compounds were tested in 10-13week old B6;CBA-Tg(ATXN3*)84.2Cce/IbezJ male and female mice (JAX®. W,Mice, The Jackson Laboratory) housed 3-5 per cage. The mice aretransgenic mice which express the human ATXN3 pre-mRNA sequence, with 84CAG repeats motif, an allele which is associated with MJD in humans).Animals were held in colony rooms maintained at constant temperature(22±2° C.) and humidity (40+80%) and illuminated for 12 hours per day(lights on at 0600 hours). All animals had ad libitum access to food andwater throughout the studies. All procedures are performed in accordancewith the respective Swiss regulations and approved by the CantonalEthical Committee for Animal Research.

Administration Route—Intra-cisterna magna injections.

The compounds were administered to mice by intra cisterna magna (ICM)injections. Prior to ICM injection the animals received 0.05 mg/kgBuprenorphine dosed sc as analgesia. For the ICM injection animals wereplaced in isofluran. Intracerebroventricular injections were performedusing a Hamilton micro syringe with a FEP catheter fitted with a 36gauge needle. The skin was incised, muscles retracted and theatlanto-occipital membrane exposed. Intracerebroventricular injectionswere performed using a Hamilton micro syringe with a catheter fittedwith a 36 gauge needle. The 4 microliter bolus of test compound orvehicle was injected over 30 seconds. Muscles were repositioned and skinclosed with 2-3 sutures. Animals were placed in a varm environment untilthey recovered from the procedure.

Two independent experiments were performed with groups of differentcompounds as shown in Table 8A.

TABLE 8A Compound ID Dose, gg Time-point Group Size Saline only 0 4 wk 61856_1 250 4 wk 8 1813_1 250 4 wk 8 1812_1 250 4 wk 8 1809_2 250 4 wk 81607_1 250 4 wk 8 1122_62 250 4 wk 8 1122_67 250 4 wk 8 1122_33 250 4 wk8

Tolerability Results:

All compounds were found to be tolerated up to the 4 weeks timepoint.Acute toxicity was measured by monitoring the animal's behavior asdescribed in WO2016/126995 (see example 9). Sub-acute toxicity wasmeasured by monitoring the body weight of each animal during the timecourse of the experiment, with >5% weight reduction indicative ofsub-acute toxicity. In some groups 1 or 2 animals did show some distressafter the ICM administration and were euthanized, but this was likely tobe due to the procedure rather than a adverse toxicity of any of thecompounds. All eight compounds were therefore considered to be welltolerated in vivo.

4 weeks post administration, the animals were sacrificed, and tissuesfrom the cortex, midbrain, cerebellum, hippocampus pons/medulla andstriatum were collected weighed and snap frozen in liquid N2 directlyafter sampling. Samples were stored on dry ice until storage at −80° C.

Analysis of in vivo samples. Description of tissue preparation forcontent measurement and qPCR.

Mouse tissue samples were homogenized in the MagNA Pure LC RNA IsolationTissue Lysis Buffer (Roche, Indianapolis, Ind.) using a QiagenTissueLyzer II. The homogenates were incubated for 30 minutes at roomtemperature for complete lysis. After lysis the homogenates werecentrifuged for 3 minutes at 13000 rpm and the supernatant used foranalysis. Half was set aside for bioanalysis and for the other half, RNAextraction was continued directly.

Oligo Content Analysis

For bioanalysis, the samples were diluted 10-50 fold for oligo contentmeasurements with a hybridization ELISA method. A biotinylatedLNA-capture probe and a digoxigenin-conjugated LNA-detection probe (both35 nM in 5×SSCT, each complementary to one end of the LNAoligonucleotide to be detected) was mixed with the diluted homogenatesor relevant standards, incubated for 30 minutes at RT and then added toa streptavidine-coated ELISA plates (Nunc cat. no. 436014).

The plates were incubated for 1 hour at RT, washed in 2×SSCT (300 mMsodium chloride, 30 mM sodium citrate and 0.05% v/v Tween-20, pH 7.0)The captured LNA duplexes were detected using an anti-DIG antibodiesconjugated with alkaline phosphatase (Roche Applied Science cat. No.11093274910) and an alkaline phosphatase substrate system (Blue Phossubstrate, KPL product code 50-88-00). The amount of oligo complexes wasmeasured as absorbance at 615 nm on a Biotek reader.

Data was normalized to the tissue weight and expressed as nM of oligo.

mRNA Analysis

RNA was purified from 350 μL of supernatant using the MagNA Pure 96instrument using the kit Cellular RNA Large Volume Kit (Roche,Indianapolis, Ind.). RNA samples were normalized to 2 ng/μL inRNase-Free water and stored at −20° C. until further use.

For one-step qPCR (cDNA synthesis and qPCR), each sample was run induplicates with four probe sets (IDT, Leuven, Belgium) run in duplex.

To each reaction 44 of previously diluted RNA, 0.54 of water and 5.54 ofTaqMan MasterMix was added. Plates were centrifuged and heat-chocked at90° C. for 40sek followed by a short incubation on ice before analyzingthe samples using qPCR (Incubation at 50° C. for 15 minutes and 90° C.for 3 minutes followed by 40 cycles at 95° C. for 5 sec and 60° C. for45 sec). Assay probes are described below.

Data was analyzed using the relative standard curve method where each isfirst normalized to the housekeeping gene (RPL4) and then expressed aspercent of untreated control animals.

qPCR assays for in vivo studies:Human ATXN3, qPR assay: (ATXN3_exon_8-9(1)PrimeTime ® XL qPCR Assay (IDT). qPCR probe and primers:(SEQ ID NO: 1134) Probe: 5′-/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCT AAGT/31ABkFQ/-3′ (SEQ ID NO: 1135)Primer 1: 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′ (SEQ ID NO: 1136)Primer 2: 5′-CATGGAAGATGAGGAAGCAGAT-3′ House keeping gene used:Mouse RPL4, qPCR assay (Mm.PT.58.17609218)PrimeTime ® XL qPCR Assay (IDT). qPCR probe and primers:(SEQ ID NO: 1090) Probe: 5′-/5HEX/CTG AAC AGC/ZEN/CTC CTT GGT CTTCTT GTA/3IABkFQ/-3′ (SEQ ID NO: 1091)Primer 1: 5′-CTT GCC AGC TCT CAT TCT CTG-3′ (SEQ ID NO: 1092)Primer 2: 5′- TGG TGG TTG AAG ATA AGG TTG A-3′

Results:

The results are shown in Table 8B.

All compounds tested gave efficacious target inhibition in the tissuestested and were tolerated at the doses tested. Compound 1122_33 acrossthe compounds tested has either the best or second ranked highestspecific activity (lower EC50) in all tissues, followed by 1122_62 and1122_67.

Compounds 1122_67, 1607_1, 1813_1 and 1122_33 provided high efficacy invivo in all tissues tested, illustrating a remarkable consistentinhibition of ATXN3 expression across the brain tissues tested. Based onan accumulative rank score compound 1122_67 was consistently either thebest or second ranked compound in terms of efficacy of ATXN3 knock downin the tissues tested.

Example 9: Testing in vitro efficacy of LNA oligonucleotides andReference Compounds in a time course, dose range experiment in humaniPSC-derived neurons Materials and Methods:

Compounds used: 1122_67 and 1813_1 & the following reference compoundsdisclosed in WO2019/217708, as referenced by the Compound ID numbersused in WO2019/217708: 1100673, 1101657, 1102130, 1103014 & 1102987.Compounds 1100673, 1101657, 1102130 are highlighted in WO2019/217708 asproviding potent in vivo inhibition, compounds 1103014 and 1102987 werenot evaluated in vivo in WO2019/217708, but are included as referencecompounds due to the sequence similarity to compound 1122_67 (1103014)and 1813_1 (1102987).

The iCell® GlutaNeurons cells were prepared and maintained as describedin Example 5 & Table 2. Cells were grown for 7 days before addition ofthe oligonucleotide in concentration of 0-10 μM (dissolved in medium).

Cells were harvested at 4 days, 6 days, 9 days, 12 days and 20 daysafter oligo treatment, and RNA extraction and qPCR was performed asdescribed for “Example 1”, using the ATXN3 primar assay described inexample 5. The relative ATXN3 mRNA expression levels were determined as% of control (medium-treated cells) i.e. the lower the value the largerthe inhibition.

Results:

The results are shown in Table 9.

TABLE 9 EC50 in hiPSC-derived neurons, nM Compound Day 4 Day 6 Day 9 Day12 Day20 1122_67 7.2 1.3 1.4 1.1 1.1 1813_1 23 6.3 10 8.9 7.7 1100673110 27 30 34 44 1101657 515 204 69 90 73 1102130 315 164 390 101 1331103014 662 64 435 98 369 1102987 944 305 135 391 200Compounds 1122_67 and 1813_1 were remarkably more potent than the 5reference compounds, with compound 1122_67 being the most potentcompound at all time points and both 1122_67 and 1813_1 gave aremarkably effective and long lasting inhibition of ATXN3 mRNA.

Example 10: Comparative In vivo transgenic mouse study Materials andMethods:

A further in vivo study was performed at Charles River Laboratories DenBosch B.V., Groningen, NL, using compound 1122_67 and 1813_1, andreference compound 1100673 (WO2019/217708). The study used male andfemale B6;CBA-Tg(ATXN3*)84.2Cce/IbezJ mice with the compoundsadministered via intracisternal (ICM) administration. At two timepointsafter compound administration, 1 or 4 weeks, animals were euthanized andterminal plasma samples and tissues were collected.

Animal Care

In vivo activity and tolerability of the compounds were tested in 62B6;CBA-Tg(ATXN3*)84.2Cce/IbezJ male and female mice (JAX® Mice, TheJackson Laboratory) at the age between 7-10 weeks. Following arrival,animals were housed in groups up to 5 in individually vented cages (IVC,40×20×16 cm) in a temperature (22±2° C.) and humidity (55±15%)controlled environment on a 12 hour light cycle (07.00-19.00 h). Malesand females were kept in separate cages. Standard diet (SDS Diets, RM1PL) and domestic quality mains water were available ad libitum. Ifrequired, animals received soaked chow and/or Royal Canin in addition toStandard diet as part of pamper care. The experiments were conducted instrict accordance with the Guide for the Care and Use of LaboratoryAnimals (National Research Council 2011) and were in accordance withEuropean Union directive 2010/63 and the Dutch law. The in vivoexperiment described was performed at Charles River Laboratories DenBosch B.V. location Groningen (Groningen, the Netherlands).

Administration Route-Intra-cisterna Magna injections.

The compounds were administered to mice by intra cisterna magna (ICM)injections. Mice were anesthetized using isoflurane (2.5-3% and 500mL/min 02). Before surgery, Finadyne (1 mg/kg, s.c.) was administeredfor analgesia during surgery and the post-surgical recovery period. Amixture of bupivacaine and epinephrine was applied to the incision siteand periost of the skull for local analgesia.

Animals were placed in a stereotaxic frame (Kopf instruments, USA) andan incision made at the back of the head towards the neck. Then, theskin was spread and the coordinates marked prior to drilling a hole inthe occipital bone of the skull, where a cannula was placed. Next, thecompounds were injected into the cisterna magna (ICM). A volume of 4 μLof the assigned test item was injected over 30 seconds. After injection,the needle and cannula were held in place for 30 seconds to ensure noback flow occurred. The cannula was then retracted, the hole was coveredwith skin and the incision was closed by sutures.

Animals were placed in a warm environment until recovered from theprocedure.

Compound 1122_67 was administered at a single dose of 90, 150 or 250 μg,and compound 1813_1 was administered at a single dose of 150 μg or 250μg. The reference compound 1100673 was administered at a single dose of250 μg only.

From three days prior to ICM injections, up to one week afteradministration, animal's weight was registered daily. Animal's weightwas monitored and registered at least twice a week for the rest of theexperiment.

At the end of the experiment, on day 8 or 29 (1 or 4 weeks), the animalswere euthanized by Euthasol® overdose. Terminal plasma was collected inLi-Hep tubes. Terminal tissues were harvested from the animals and weredissected on a chilled surface. Half of the tissue samples were storedin 2.0 mL Safe-Lock tubes, PCR clean, pre-weighted and precooled.Immediately after collection, samples were weighed and flash frozen inliquid N2 prior to storage at −80° C. The other half was fixed in 4% PFAfor 72 hours and subsequently transferred to 70% ethanol awaitingshipment. Tissue dissection and collection was performed, collectingtissue from a range of tissues: Midbrain, Cortex, Striatum, Hippocampus,Cerebellum, Brainstem, and spinal cord (Cervical, Thoracic & Lumbar).

Tolerability Results:

Acute toxicity was measured by monitoring the animal's behavior asdescribed in WO2016/126995 (see example 9). Chronic toxicity wasmeasured by monitoring the body weight of each animal during the timecourse of the experiment, with >5% weight reduction indicative ofchronic toxicity. In some groups 1 or 2 animals did show some distressafter the ICM administration and were euthanized, but this was likely tobe due to the nature of the surgical procedure rather than a adversetoxicity of any of the compounds.

There were signs of acute toxicity at the 250 μg dose of 1813_1 in 3mice, leading to early euthanisation of this group of animals. Otherwiseall compounds were found to be tolerated up to the 4 weeks timepoint.

After 4 weeks the animals were euthanised and brain and CNS tissuecollected: Spinal cord, cortex, striatum, hippocampus, midbrain,brainstem and cerebellum as well as liver and kidney was collected inliquid nitrogen for drug concentration analysis an ATAXN3 mRNA analysisat 1 or 4 weeks following dosing.

Analysis of in vivo samples: Description of tissue preparation forcontent measurement and qPCR was performed as per Example 8. The EC50was calculated, and maximum KD achieved recorded this data is providedin Table 10.

Results:

Compound 1122_67 was the most effective compound in all brain tissuestested and gave an excellent effective knock-down in all brain tissuestested, indicating good bio-distribution to all key tissues (1813_1 wasas effective as 1122_67 in spinal cord, brainstem and midbrain). Notablycompound 1122_67 gave highly effective knock-down in cerebellum, atissue which the reference compound 1100673 was notably less effective.A further key observation at the after 4 weeks of treatment is that theefficacy of 1122_67 was even further improved as compared to the 1 weektimepoint in all brain tissues. Notably, the efficacy of the referencecompound, 1100673 was notably lower at the 4 week stage vs. the 1 weektimepoint, particularly in key cerebellum and cortex tissues. The longduration of action and high potency of 1122_67 indicates that thiscompound should require a less frequent administration in a therapeuticsetting.

Example 11: Compound Stability to SVPD Materials and Methods:

3′—exonuclease snake venom phosphodiesterase I (SVP) (Art. No. LS003926,Lot. No. 58H18367) was purchased by Worthington Biochemical Corp.(Lakewood, N.Y., USA). The reaction mix for the 3′—exonuclease snakevenom phosphodiesterase I (SVP) assay consisted of 50 mM TRIS/HCl pH 8buffer, 10 mM MgCl2, 30 U CIP (NEB, Ipswich, Mass., USA), 0.02 U SVP andthe oligonucleotide compound. The stability of the ASOs against SVPD wasdetermined by performing the nuclease assays over a one day time course.In each reaction mix an amount about 0.2 mg/mL ASO in a totaly volume of150 μl was used.

The incubation period of 24 h at 37° C. was performed on an autosampler,the SVPD and reactions and the ASO stabilities were monitored in timeintervals by an UHPLC system equipped with a diode-array detector andcoupled with electrospray ionization-time of flight mass spectrometry(ESI-ToF-MS). To generate the t=0 h time point, the enzyme was addedinto the reaction mix, directly before the first injection. Furtherinjections took place at regular intervals over a period of 24 hours.

Compounds tested, 1122_67, 1813_1 and the reference compounds 1100673,1101657, 1102130, 1103014, and 1102987.

Results:

The data is illustrated in FIG. 9. Whilst the three highlightedreference compounds from WO2019/217708 and the 1122_67 and 1813_1compounds had good stability in the SVPD assay, the 2 referencecompounds from WO2019/217708 with the closest sequence to 1122_67 and1813_1, compounds 1103014 and 1102987 were notably more vulnerable toSVPD degradation as compared to 1122_67 and 1813_1.

Example 12: WT and polyQ Ataxin 3 protein levels in human SCA3 patientderived fibroblasts treated with selected oligonucleotides (ASO)Materials and Methods:

This experiment was performed to investigate the efficacy of effiacty ofknock down of the LNA oligonucleotides, 1122_67 and 1122_33, as comparedto the prior art compounds, 1100673 and 1102130 in SCA3 patient derivedfibroblasts, allowing for an assessment of the efficacy on the diseasecausing ataxin3 allele and the ataxin3 WT allele.

Cell line used for the ASO treatment, human SCA3 patient derivedfibroblasts (GM06153 Coriell Institute). One hundred thousand cells wereseeded per well in a 24 well plate with a total volume of 1 ml. ASOswere added immediately after to a final concentration of 10 μM (gymnoticuptake). After 4 days of incubation at, cells were washed twice withPBS, and harvested in 200 μl RIPA buffer (Thermo Scientific, Pierce).

Western blots were performed on the capillary-based immunoassay platform(WES, ProteinSimple) using a WES 12-230 kDa Wes Separation Module. Celllysate were diluted 10×in Sample load buffer (ProteinSimple) priorloading on the cartridge. Primary antibody for Ataxin 3 (rabbitmonoclonal antibody, prod. #702788 from Invitrogen) and for HPRT (rabbitmonoclonal antibody, cat. #Ab109021 from Abcam). Both antibodies wereused in 1/100 dilutions. Goat anti-rabbit HRP conjugate (Part. #DM-001,ProteinSimple) was used as secondary antibody.

Compass software (ProteinSimple) was for quantification of the proteinbands.

Results:

To show an efficient KD of both the wild type as well as the polyQextended Ataxin 3 protein, GM06153 cells were treated with 10 uM of ASOfor four days prior to protein analysis on the WES. Ataxin 3 antibodyrecognize both isoforms, and the intensity (area under peak) wasnormalized to the protein input based on the signal from HPRT. As seenfrom the FIGS. 10A and B, we observe that upon treatment with 1122_67and 1122_33, there is an increased reduction in the polyQ extendedAtaxin 3 compared to the wild type Ataxin 3. This trend is not observedfor the other ASOs (Scrambled control, 1100673 or 1102130) where weobserve a higher amount of the polyQ extended Ataxin 3, compared to thewild type Ataxin 3. A higher activity on the disease causing polyQextended Ataxin 3 than the WT Ataxin 3 is preferable as it allows aselective reduction of the disease causing allele.

Example 13: Redesign library Materials and Methods:

Compound ID Nos. 1122_67 and 1122_33 were used as parents in a redesignlibrary. The compounds in the redesign library differed from the parentcompounds and each other in intemucleoside linkages and/or thenucleosides used. In general, nucleosides at specific positions werevaried between LNA, DNA and nucleoside analogs with differentmodifications in the 2′ position in the ribose. The intemucleosidelinkages were otherwise phosphorothioate linkages. In some compounds,the chirality was controlled by use of phosphorothioate linkagesproviding for sterodefined backbones. The modifications employed areillustrated below.

The compounds of the redesign library are listed in Table 11, where thestructure of each compound is described by the hierarchical editinglanguage for macromolecules (HELM) (for details, see Zhang et al., Chem.Inf. Model. 2012, 52, 10, 2796-2806) using the following HELM annotationkeys:

-   -   [LR](G) is a beta-D-oxy-LNA guanine nucleoside,    -   [LR](T) is a beta-D-oxy-LNA thymine nucleoside,    -   [LR](A) is a beta-D-oxy-LNA adenine nucleoside,    -   [LR]([5meC] is a beta-D-oxy-LNA 5-methyl cytosine nucleoside,    -   [dR](G) is a DNA guanine nucleoside,    -   [dR](T) is a DNA thymine nucleoside,    -   [dR](A) is a DNA adenine nucleoside,    -   [dR]([C] is a DNA cytosine nucleoside,    -   [sP] is a phosphorothioate internucleoside linkage (stereo        undefined)    -   [ssP] is a stereodefined Sp phosphorothioate internucleoside        linkage    -   [mR](G) is a 2′-O-methyl guanine nucleoside,    -   [mR](U) is a 2′-O-methyl uracil nucleoside,    -   [mR](A) is a 2′-O-methyl adenine nucleoside,    -   [mR](C) is a 2′-O-methyl cytosine nucleoside,    -   [MOE](G) is a 2′-O-methoxyethyl guanine nucleoside,    -   [MOE](T) is a 2′-O-methoxyethyl thymine nucleoside,    -   [MOE](A) is a 2′-O-methoxyethyl adenine nucleoside,    -   [MOE]([5meC]) is a 2′-O-methoxyethyl 5-methyl cytosine        nucleoside,    -   [fR](G) is a 2′-fluoro guanine nucleoside,    -   [fR](U) is a 2′-fluoro uracil nucleoside,    -   [fR](A) is a 2′-fluoro adenine nucleoside,    -   [fR](C) is a 2′-fluoro cytosine nucleoside.

Results:

In Table 11, a compound with a compound ID number “1122_” or “1816_” isa modified version of SEQ ID NO:1122 or SEQ ID NO:1816, respectively.

TABLE 11 Compound and HELM table CMPIDNO HELM 1122_82[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[MOE]([5meC])[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_83[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[mR](U)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_84[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[mR](U)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_85[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[mR](U)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_86[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[mR](U)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_87[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[mR](U)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]• [LR]([5meC]) 1122_88[LR](A)[sP]•[dR](A)[sP]•[mR](U)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]• [LR]([5meC]) 1122_89[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[mR](U)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_90[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[mR](U)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_91[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[mR](U)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](C)[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 1122_92[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[dR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[MOE]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR]([5meC])[sP]•[LR]([5meC]) 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C])[sP]•[LR](T)[sP]•[LR](T)1816_71[LR](G)[sP]•[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR](A)[sP]•[dR](T)[sP]•[fR](U)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[LR](T)[sP]•[LR](T)1816_72[LR](G)[sP]•[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR](A)[sP]•[fR](U)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[LR](T)[sP]•[LR](T)1816_73[LR](G)[sP]•[LR](A)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[fR](U)[sP]•[LR](T)[sP]•[LR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[LR](T)[sP]•[LR](T)1816_74[LR](G)[sP]•[LR](A)[sP]•[dR](A)[sP]•[fR](U)[sP]•[LR]([5meC])[sP]•[dR](T)[sP]•[LR](T)[sP]•[LR](A)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[dR](T)[sP]•[LR]([5meC])[sP]•[LR](T)[sP]•[LR](T)

Example 14: Testing in vitro efficacy of LNA oligonucleotides in iCell®GlutaNeurons at 1.25 μM and 62.5 nM Materials and Methods:

The compounds of the redesign library described in Table 11 of Example13 were evaluated for potency in human iPSC cells using twoconcentrations; 1.25 μM and 62.5 nM, comparing the effect on the ATXN3transcript and the KCNB2 transcript at both concentrations.

The iCell GlutaNeuron cells were prepared and maintained essentially asdescribed in Example 5 & Table 2. 96-well cell culture plates werecoated with Poly-L-Ornithine (0.01%) (Sigma-P4957), 100μl/well for 4hours. Rinsed 3 times with PBS and coated with Laminin (RocheDiagnostic, 11243217001) 0.5 mg/ml diluted 1:500 in PBS overnight at 4degrees Celsius. The cells were treated and maintained as perrecommendation by the vendor using the provided protocol: iCell®GlutaNeurons, User's Guide, Document ID: X1005, Version 1.2, CellularDynamics, Fujifilm; available at https: addresscdn.stemcell.com/media/files/manual/MADX1005-icell_glutaneurons_users_guide.pdf(accessed on e.g. 10 Nov. 2020). Compounds were added to the cells frompre-dilution plates (compound diluted in PBS) to reach the desired finalconcentration. RNA purification and qPCR were performed as described inExample 2; however, using the qPCR assays described below for analysis.

Human KCNB2 pre-mRNA using the qPCR assay:“Hs.PT.58.39309562”, PrimeTime ® XL qPCR Assay(Integrated DNA Technologies (IDT), Leuven, Belgium) (SEQ ID NO: 1989)Probe: 5′-/56-FAM/AGA AAC CTA/ZEN/ACT CAT CAG TGG CTG CAA/3IABkFQ/-3′(SEQ ID NO: 1990) Primer 1: 5′-GAA CAG GAT AGA CAC GAT GGC-3′(SEQ ID NO: 1991) Primer 2: 5′-AGA GAC TAT GCG AGA GCG A-3′Human ATXN3 pre-mRNA using the qPCR assay: costumdesign “(ATXN3_exon_8-9(1)”, PrimeTime ® XL qPCR Assay (IDT).(SEQ ID NO: 1134) Probe: 5′-/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCTAAGT/31ABkFQ/-3′ (SEQ ID NO: 1135)Primer 1: 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′ (SEQ ID NO: 1136)Primer 2: 5′-CATGGAAGATGAGGAAGCAGAT-3′Human TBP pre-mRNA using the qPCR assay:“Hs.PT.58v.39858774”, PrimeTime ® XL qPCR Assay (IDT) (SEQ ID NO: 1131)Probe: 5′-/5HEX/TGA TCT TTG/ZEN/CAG TGA CCC AGC ATC A/3IABkFQ/-3′(SEQ ID NO: 1132) Primer 1: 5′-GCT GTT TAA CTT CGC TTC CG-3′(SEQ ID NO: 1133) Primer 2: 5′-CAG CAA CTT CCT CAA TTC CTT G-3′

Results:

The results from this screen is presented in Table 12 as the level ofremaining transcript with values given in percent (%) relative tountreated cells, i.e. low level means efficient knockdown. This was donefor each of the applied concentrations for each of the two target genes(ATXN3 and KCNB2). Most of the tested compounds showed efficaciousknockdown of the ATXN3 transcript at both concentrations used. Theeffect on the KCNB2 transcript was variable.

TABLE 12 1.25 uM (% 62.5 nM (% 1.25 uM (% 62.5 nM (% ATXN3 ATXN3 KCNB2KCNB2 CMP ID mRNA mRNA mRNA mRNA NO remaining) remaining) remaining)remaining) 1122_33  14.84 41.69 66.57 88.67 1122_67  15.03 39.41 9.9359.09 1122_82  18.29 50.93 17.61 73.26 1122_83  18.12 54.07 84.73 96.231122_84  12.59 40.95 27.66 74.71 1122_85  15.13 40.70 23.47 82.111122_86  16.64 53.29 75.13 113.41 1122_87  13.46 35.67 19.90 69.291122_88  12.85 34.25 24.41 68.38 1122_89  16.45 46.10 38.00 75.091122_90  18.52 50.88 60.64 93.90 1122_91  17.83 45.26 35.19 86.041122_92  15.49 41.46 21.27 68.79 1122_93  65.98 89.20 90.58 103.351122_94  63.83 92.70 82.15 98.30 1122_95  15.40 35.25 6.65 49.081122_96  16.51 44.63 2.69 48.45 1122_97  37.79 65.35 42.78 75.621122_98  14.34 38.27 0.91 42.75 1122_99  33.48 58.08 25.62 69.291122_100 12.21 31.92 0.85 44.41 1122_101 15.41 46.59 60.45 90.561122_102 15.62 41.71 16.98 62.88 1122_103 14.11 37.53 2.61 46.871122_104 18.01 47.10 36.56 81.02 1122_105 18.20 43.65 19.99 74.461122_106 16.64 36.77 7.75 55.14 1122_107 14.84 41.59 32.47 69.471122_108 12.89 32.26 8.10 72.49 1122_109 15.35 35.47 2.01 57.70 1122_11019.02 45.56 0.72 45.61 1122_111 55.00 73.98 36.41 88.13 1122_112 16.3840.70 0.77 50.17 1122_113 29.42 56.92 17.68 60.51 1122_114 13.63 33.670.43 42.62 1122_115 18.86 46.13 57.49 98.41 1122_116 31.73 59.42 28.4486.09 1122_117 26.55 55.77 10.27 67.46 1122_118 49.24 68.77 52.70 88.131122_119 19.51 44.68 9.36 60.99 1122_120 16.50 40.36 2.16 51.59 1122_12116.61 40.45 5.55 56.34 1122_123 15.49 38.63 0.95 52.77 1122_124 28.9054.57 17.31 68.48 1122_125 15.75 41.51 12.29 63.50 1122_126 15.68 44.309.96 63.90 1122_127 14.91 45.71 9.92 55.07 1122_128 18.12 46.12 20.9879.79 1122_129 15.62 44.07 9.19 69.22 1122_130 14.90 43.91 8.27 68.501122_131 17.75 46.92 20.03 67.67 1122_132 17.93 41.86 8.22 72.391122_133 18.11 47.91 14.60 78.23 1122_134 17.42 48.52 14.02 61.731122_135 14.62 46.43 3.71 52.73 1122_136 16.28 35.03 8.48 56.82 1122_13714.92 37.45 12.42 65.30 1122_138 14.40 37.58 14.48 63.64 1122_139 15.0638.30 14.21 66.30 1122_140 14.40 37.78 18.42 63.01 1122_141 16.19 37.6416.31 64.03 1122_142 15.90 40.17 15.61 61.47 1122_143 14.70 103.24 12.58109.05 1122_144 15.85 38.70 24.26 63.50 1122_145 14.15 36.53 13.02 67.511122_146 15.95 38.11 20.70 69.38 1122_147 15.08 40.89 19.48 62.041122_148 17.05 37.47 15.74 57.67 1122_149 15.43 35.40 43.92 78.041122_150 14.10 34.07 43.11 82.00 1122_151 15.65 37.73 48.08 92.951122_152 13.89 33.97 32.02 83.04 1122_153 13.97 35.53 40.47 82.391122_154 13.75 34.07 35.44 86.80 1122_155 14.15 43.77 43.08 83.801122_156 15.13 37.99 44.64 87.46 1122_157 14.34 40.19 57.37 88.721122_158 13.68 35.71 42.68 80.61 1122_159 15.47 40.55 57.30 86.781122_160 13.51 38.20 36.47 80.75 1122_161 15.52 42.53 10.78 64.301122_162 16.08 46.05 43.50 90.89 1122_163 17.28 45.49 42.75 86.761122_164 33.44 63.29 64.52 94.34 1122_165 29.00 63.38 67.97 84.551122_166 16.50 50.60 37.71 85.58 1122_167 12.92 42.08 37.91 76.461122_168 17.21 53.77 74.23 98.46 1122_169 13.00 41.35 17.57 69.241122_170 15.62 48.53 71.05 92.86 1122_171 12.95 35.94 10.80 59.511122_172 14.15 40.39 30.00 76.26 1122_173 16.04 48.13 50.42 95.731122_174 16.06 46.62 27.28 75.84 1122_175 17.19 41.23 44.35 89.611122_176 12.72 38.58 24.65 74.88 1122_177 43.57 68.03 56.40 78.381122_178 18.39 48.85 7.77 60.36 1122_179 12.21 36.54 0.66 39.24 1122_18011.41 29.30 2.53 50.10 1122_181 11.39 29.60 1.37 45.39 1122_182 11.9133.43 1.00 38.58 1122_183 15.53 53.20 70.04 89.74 1122_184 18.29 50.2571.87 94.73 1122_185 12.42 38.65 16.98 64.32 1122_186 15.43 35.73 0.6038.92 1122_188 95.10 91.87 98.34 92.17 1122_189 13.17 45.93 42.56 81.861122_190 88.24 96.08 101.92 93.17 1122_191 17.43 47.23 35.22 84.241122_192 14.50 41.74 2.75 47.15 1122_193 17.94 45.59 16.35 70.521122_194 19.14 42.96 2.51 44.63 1122_195 15.03 41.04 6.84 58.60 1122_19614.86 39.28 0.98 47.63 1122_197 14.80 39.13 0.62 45.40 1122_198 23.6854.40 20.87 71.13 1122_199 22.98 50.51 18.55 67.76 1122_200 23.58 50.6237.86 81.81 1122_201 19.40 46.35 7.15 59.27 1122_202 18.20 46.98 5.7854.72 1122_203 17.69 45.67 2.10 48.19 1122_204 13.49 37.08 0.50 43.421122_205 115.04 44.88 5.19 83.93 1122_206 12.85 35.68 1.05 52.131122_207 16.58 45.34 58.08 97.54 1122_208 17.59 47.72 13.12 61.521122_209 18.16 44.97 35.65 72.69 1122_210 17.36 47.09 30.36 68.941122_211 19.96 46.56 20.87 72.34 1122_212 24.09 54.75 49.10 83.351122_213 18.37 48.15 27.49 74.55 1122_214 14.29 39.30 15.92 66.141122_215 15.37 38.56 2.04 41.18 1122_216 15.01 42.66 7.02 58.95 1122_21717.30 46.90 32.59 82.10 1122_218 13.77 42.95 25.43 71.68 1122_219 12.8737.59 17.95 52.45 1122_220 13.52 38.61 1.85 48.48 1122_221 18.36 45.4729.00 75.06 1122_222 23.95 54.80 19.25 67.91 1122_223 19.96 48.20 33.5074.16 1122_224 68.09 95.88 81.06 104.47 1122_225 31.31 66.62 53.44 90.701122_226 102.33 93.40 96.03 101.72 1122_227 17.68 49.92 63.44 98.061122_228 12.94 28.36 0.52 40.67 1122_229 13.82 36.60 25.36 83.321122_230 13.78 29.77 1.16 53.35 1122_231 13.75 34.55 14.04 67.821122_232 12.79 33.53 16.70 73.24 1122_233 11.52 28.88 0.67 39.961122_234 12.10 29.35 0.12 30.89 1122_235 10.75 31.37 1.35 45.12 1122_23615.54 36.00 19.38 78.46 1122_237 14.85 38.11 20.56 76.35 1122_238 98.98100.70 93.56 109.21 1122_239 18.93 56.23 59.59 93.71 1122_240 14.8038.69 0.90 42.40 1122_241 15.37 46.65 20.38 66.87 1122_242 15.24 42.1013.87 68.39 1122_243 15.73 44.21 14.67 66.50 1122_244 14.11 40.27 0.8639.99 1122_245 13.14 33.83 0.38 39.46 1122_247 12.86 33.71 0.90 43.551122_248 90.91 95.53 106.59 91.46 1122_249 14.22 41.84 40.90 87.001122_250 90.31 100.03 100.46 97.45 1122_251 102.82 102.41 98.63 99.261122_252 16.50 48.66 38.13 85.83 1122_253 17.79 48.73 31.96 79.201122_254 16.26 46.83 26.68 70.97 1122_255 16.23 39.36 1.22 48.881122_256 18.48 44.91 7.37 62.07 1122_257 18.72 43.81 1.85 49.52 1122_25828.90 59.55 22.76 80.32 1122_259 13.02 35.53 0.27 37.49 1122_260 39.0364.19 25.97 75.30 1122_261 25.96 54.58 4.80 54.40 1122_262 64.09 79.1548.38 86.81 1122_263 41.44 64.92 14.48 60.49 1122_264 31.93 53.80 8.8657.82 1122_265 21.30 46.83 1.90 48.70 1122_266 12.74 38.89 0.38 39.261122_267 13.34 34.60 0.35 35.53 1122_268 21.75 52.36 45.71 88.451122_269 15.62 34.21 0.99 42.01 1122_270 18.23 48.08 55.25 92.411122_271 29.49 58.90 12.49 74.08 1122_272 22.71 53.62 17.96 86.691122_273 30.84 63.97 39.74 79.91 1122_274 25.06 55.33 14.72 72.241122_275 46.36 77.28 49.33 91.76 1122_276 22.07 52.96 22.13 75.391122_277 24.76 52.41 2.80 104.85 1122_278 16.09 39.55 1.05 53.391122_279 16.97 41.64 2.59 53.82 1122_280 19.16 47.62 53.88 89.201122_281 15.33 35.15 1.21 49.25 1122_282 18.74 46.47 19.18 70.601122_283 14.21 38.75 0.92 49.39 1122_284 21.36 50.04 17.88 77.201122_285 24.58 53.16 11.30 69.32 1122_286 26.61 59.28 32.18 85.201122_287 19.11 46.43 40.68 87.49 1122_288 17.38 46.11 29.23 83.511122_289 22.65 50.00 18.22 80.28 1122_290 15.73 46.26 46.94 97.941122_291 17.59 47.83 57.89 97.49 1122_292 18.87 45.34 51.24 76.101122_293 19.91 50.35 80.98 93.18 1122_294 15.68 44.72 63.82 89.721122_295 17.72 46.95 72.65 97.04 1122_296 18.22 45.33 84.64 65.091122_297 21.12 52.34 55.13 90.63 1122_298 19.04 49.85 43.05 83.361122_299 21.00 53.98 52.09 88.91 1122_300 21.03 56.31 63.83 96.361122_301 15.75 41.51 15.41 71.45 1122_302 15.98 41.88 33.75 82.191122_303 14.92 33.22 16.97 73.97 1122_304 12.17 33.01 0.96 54.411122_305 17.66 38.97 1.49 58.34 1122_306 18.52 42.72 3.38 58.51 1122_30742.52 62.86 49.15 83.10 1122_308 15.75 46.33 18.59 81.21 1122_309 18.6946.63 43.91 88.58 1122_310 21.63 49.10 64.20 92.07 1122_311 15.23 36.710.82 55.64 1122_312 16.28 40.30 14.72 71.61 1122_313 17.13 42.41 26.1478.29 1122_314 17.15 44.16 17.44 74.43 1122_315 15.87 37.68 3.87 56.291122_316 12.46 40.91 15.99 79.86 1122_317 19.92 51.35 75.13 91.761122_318 19.72 55.90 84.62 96.07 1122_319 14.89 40.90 30.49 84.121122_320 14.12 38.83 35.60 80.47 1122_321 16.55 47.64 39.44 85.961122_322 19.89 46.85 51.06 83.91 1122_323 16.91 39.33 31.59 85.791122_324 13.32 34.73 23.93 76.58 1122_325 13.64 36.88 34.23 82.541122_326 17.03 47.80 65.51 93.50 1122_327 13.18 34.45 0.61 41.051122_328 28.85 51.75 33.40 73.68 1122_329 18.98 45.02 9.68 55.711122_330 26.09 52.37 29.65 77.91 1122_331 19.50 48.30 9.77 63.781122_332 17.96 54.05 7.57 72.56 1122_333 18.01 45.82 5.15 54.92 1122_33416.51 45.70 5.62 58.84 1122_335 15.28 35.40 5.27 59.31 1122_336 18.1845.30 24.99 75.94 1816_2  60.44 75.00 72.19 101.12 1816_3  32.49 64.7281.52 99.97 1816_4  20.62 53.39 86.99 94.28 1816_5  28.44 63.88 87.90101.86 1816_6  22.90 52.87 82.34 95.59 1816_7  80.07 88.95 93.22 101.921816_8  43.52 67.76 96.84 104.02 1816_9  21.44 54.71 92.27 103.411816_10  17.09 49.44 76.99 95.59 1816_11  21.06 53.06 78.28 98.391816_12  20.06 55.59 84.79 102.08 1816_13  17.14 48.05 93.50 100.401816_14  19.55 59.40 90.51 105.28 1816_15  22.72 59.25 101.19 106.471816_16  24.44 62.31 96.03 102.54 1816_17  22.53 55.69 91.49 101.211816_18  21.46 53.93 85.50 99.48 1816_19  21.31 54.40 87.10 95.061816_20  23.72 53.87 92.47 105.09 1816_21  19.76 50.72 89.60 105.931816_22  95.15 104.15 102.13 103.05 1816_24  91.75 95.00 98.28 102.021816_25  56.04 88.36 86.52 109.26 1816_26  102.21 101.78 105.12 108.001816_27  24.15 67.01 92.61 99.83 1816_28  21.76 57.39 101.49 98.461816_29  30.53 72.76 99.75 98.54 1816_30  24.86 57.27 74.75 84.151816_31  41.00 72.35 106.54 101.47 1816_32  21.68 53.64 83.45 100.281816_33  36.10 74.71 78.48 109.62 1816_34  43.48 68.78 90.47 99.531816_35  78.05 89.09 93.93 96.53 1816_36  81.65 87.07 91.10 97.061816_37  62.87 82.62 96.63 102.82 1816_38  34.50 62.63 88.71 98.471816_39  17.06 43.55 68.41 91.25 1816_40  22.42 59.75 58.94 93.821816_41  24.34 60.50 78.94 94.74 1816_42  17.21 51.49 88.87 106.711816_43  15.45 48.67 93.79 96.40 1816_44  27.69 62.14 89.86 98.761816_45  28.43 62.53 93.60 104.83 1816_46  38.65 95.31 99.48 95.341816_47  39.25 73.69 85.32 99.46 1816_48  72.88 95.79 95.86 105.231816_49  42.05 72.73 95.26 95.07 1816_50  24.87 61.64 93.95 95.411816_51  24.13 58.48 94.87 86.45 1816_52  19.07 46.64 61.73 103.501816_53  24.65 59.39 95.95 103.39 1816_54  18.52 50.37 75.25 100.651816_55  21.38 55.81 80.93 97.54 1816_56  23.72 74.56 81.95 94.121816_57  31.08 63.23 97.13 97.12 1816_58  26.25 60.06 82.44 91.631816_59  38.54 74.45 96.86 99.10 1816_60  21.27 53.40 102.79 95.991816_61  22.84 55.21 84.32 108.50 1816_62  28.18 66.34 89.02 100.921816_63  22.52 58.32 99.09 104.39 1816_64  17.21 48.69 101.88 109.051816_65  18.02 48.71 97.59 108.12 1816_66  24.48 59.70 98.74 91.481816_67  25.08 60.20 102.17 102.41 1816_68  18.20 52.03 93.53 107.271816_69  28.58 64.76 100.03 95.56 1816_70  32.32 65.70 93.94 104.281816_71  47.83 78.25 89.25 109.07 1816_72  35.33 62.27 91.64 107.721816_73  20.55 98.77 85.68 103.65 1816_74  26.71 60.10 87.66 99.83

Example 15: In vitro toxicity evaluation caspase assays Materials andMethods:

Based on the results in Table 12, the compounds most potent in targetingATXN3 with the least effect on KCNB2 were selected for toxicityevaluation in two caspase activation assays (see Dieckmann et al.,Molecular Therapy: Nucleic Acids Vol. 10 Mar. 2018, pp 45-54);respectively conducted in HepG2 cells (“HEPG2”) and 3T3 cells (“3T3”),Results:

The results are shown in Table 13. Using the same scoring criteria as inExample 7, the vast majority of the compounds were found safe in thetoxicity assessment. In the “HEPG2” assay, compound 1816_52 had a scoreof 0.5, compounds 1816_30 and 1816_40 a score of 1, and compound 1816_39a score of 3. In the “313” assay, the compounds with a score of 0.5were: 1816_11, 1816_74, and 1816_30; the compounds with a score of Iwere: 1816_54 and 1816_10; the compound with a score of two was:1816_52; and the compounds with a score of three were: 1816_40 and1816_39.

TABLE 13 HepG2 3T3 EC50 EC50 EC50 ratio Assay Assay ATXN3 KCNB2 (KCNB2/CMPIDNO score score (nM) (nM) ATXN3) 1122_33 0 0 103.7 2330 22.5 1122_670 0 71.09 155.40 2.20 1122_91 0 0 87.73 673.50 7.68  1122_107 0 0 89.93789.00 8.77  1122_125 0 0 81.85 98.95 1.2  1122_144 0 0 103.10 515.605.00  1122_146 0 0 93.11 490.10 5.26  1122_149 0 0 62.77 766.80 12.22 1122_150 0 0 89.36 808.50 9.05  1122_151 0 0 75.71 654.80 8.65 1122_152 0 0 66.09 662.20 10.02  1122_153 0 0 84.38 1208.00 14.32 1122_154 0 0 64.22 820.00 12.77  1122_155 0 0 75.16 1303.00 17.34 1122_156 0 0 55.26 736.10 13.32  1122_157 0 0 71.27 1658.00 23.26 1122_158 0 0 53.18 1217.00 22.88  1122_159 0 0 92.93 1472.00 15.84 1122_160 0 0 57.47 791.50 13.77  1122_163 0 0 98.81 564.40 5.71 1122_167 0 0 87.59 763.60 8.72  1122_172 0 0 67.13 465.70 6.94 1122_175 0 0 127.90 1277.00 9.98  1122_218 0 0 87.76 311.80 3.55 1122_294 0 0 93.12 2338.00 25.11  1122_296 0 0 114.80 8032.00 69.97 1122_302 0 0 104.10 682.80 6.56  1122_313 0 0 90.50 418.70 4.63 1122_319 0 0 70.04 408.20 5.83  1122_320 0 0 87.66 364.50 4.16 1122_323 0 0 99.59 720.60 7.24  1122_325 0 0 90.83 585.40 6.45 1816_4 0 0 200.90 248307.00 1235.97 1816_6  0 0 261.00 26826.00 102.78 1816_9 0 0 224.00 3280.00 14.64 1816_10 0 1 — — — 1816_11 0 0.5 — — — 1816_12 00 110 27238 247.6 1816_13 0 0 129.30 36344.00 281.08 1816_14 0 0 181.102262.00 12.49 1816_15 0 0 159.80 18449.00 115.45 1816_17 0 0 208.9033758.00 161.60 1816_18 0 0 138.40 322538.00 2330.48 1816_19 0 0 180.40107214.00 594.31 1816_20 0 0 299.50 279468.00 933.12 1816_21 0 0 203.0016057.00 79.10 1816_28 0 0 141.10 10000.00 70.87 1816_30 1 0.5 — — —1816_32 0 0 170.80 13406.00 78.49 1816_39 3 3 — — — 1816_40 1 3 — — —1816_41 0 0 154.50 12106.00 78.36 1816_42 0 0 134.60 63672.00 473.051816_43 0 0 89.79 569489.00 6342.45 1816_51 0 0 239.70 9150.00 38.171816_52 0.5 2 — — — 1816_53 0 0 392.80 35864.00 91.30 1816_54 0 1 — — —1816_55 0 0 209.00 7219.00 34.54 1816_58 0 0 259.00 23941.00 92.441816_60 0 0 167.10 67695.00 405.12 1816_61 0 0 165.20 22618.00 136.911816_63 0 0 263.00 19355.00 73.59 1816_64 0 0 127.00 5929.00 46.691816_65 0 0 99.75 36592.00 366.84 1816_66 0 0 351.30 3822.00 10.881816_67 0 0 — — — 1816_68 0 0 177.80 112276.00 631.47 1816_74 0 0.5 — ——

Example 16: Determination of EC50 values for ATXN3 and KCNB2 in iCell®Glutaneurons Materials and Methods:

Compounds were assessed in an EC50 determination in iCell Glutaneuronsincluding compound 1122_67 and 1122:33. The experimental setup was thesame as described in Example 14, except that the following compoundconcentrations were used (nM): 31.6; 10; 3.2; 1; 0.32; 0.1; 0.03; 0.01(8-step half-log).

Results:

The resulting EC50 values for ATXN3 and KCNB2 as well as the resultingratio between the EC50 values (KCNB2/ATXN3) are shown in Table 13. Fromthe data generated, it was observed that the compounds showed anincreased ratio between the determined EC50 values for KCNB2 and ATXN3as compared to compound 1122_67. The potency of the compounds on ATXN3knockdown was relatively maintained for most compounds while it wasdecreased (higher EC50 value) for all compounds when focusing on thepotency on KCNB2 knockdown.

Based on the data in Table 12 (double point determination) and Table 13(caspase in vitro toxicity; EC50 for ATXN3 knock down and the ratiobetween KCNB2 and ATXN3 EC50 values). 23 compounds (shown in Table 14and in FIG. 12) were selected based on their safety (caspase scoresabove 0 were discontinued), high potency and efficacy in ATXN3inhibition, selectivity (i.e., high ratio between KCNB2/ATXN3 EC50values) as well as their chemical diversity.

The base sequence, sugar sequence and backbone sequence features of theselected compounds are shown in Table 14, using the HELM-dictionaryshown below (see Example 13 for more detailed HELM annotations).

Base sequence Sugar sequence Backbone sequence A: (A) D: [dR] S: [ssP]C: (C) F: [fR] X: [sP] E: (5meC) L: [LR] G: (G) M: [MOE] T: (T) O: [mR]U: (U)

TABLE 14 Selected compounds CMPIDNO Base sequence Sugar sequenceBackbone sequence FIG. 1122_91 AATETTATTUACATCTTEE LDDLDLDDDODDDDDDLLLXXXXXXXXXXXXXXXXXX 12A 1122_107 AAUETTATTTACATCTTEE LLOLDDDDDDDDDDDLDLLXXXXXXXXXXXXXXXXXX 12B 1122_154 AATETTATTTACATCTTEE LDDLDLDDDDDDDDDDLLLXXXXXXXXXXSXXXXXXX 12C 1122_155 AATETTATTTACATCTTEE LDDLDLDDDDDDDDDDLLLXXXXXXXXXXXSXXXXXX 12D 1122_156 AATETTATTTACATCTTEE LDDLDLDDDDDDDDDDLLLXXXXXXXXXXXXSXXXXX 12E 1122_157 AATETTATTTACATCTTEE LDDLDLDDDDDDDDDDLLLXXXXXXXXXXXXXSXXXX 12F 1122_158 AATETTATTTACATCTTEE LDDLDLDDDDDDDDDDLLLXXXXXXXXXXXXXSXXXX 12G 1122_167 AATETTATTTACATCTTEE LDDLDLMDDDDDDDDDLLLXXXXXXXXXXXXXXXXXX 12H 1122_172 AATETTATTTACATCTTEE LDDLDLDDDDDDDDODLLLXXXXXXXXXXXXXXXXXX 12I 1122_175 AATETTATTTACATCTTEE LDDLDLDDDDODDDDDLLLXXXXXXXXXXXXXXXXXX 12J 1122_294 AATETTATTTACATCTTCE LDDLDLDDDDDDDDDDLFLXXXXXXXXXXXXXXXXXX 12K 1122_296 AATCTTATTTACATCTTEE LDDODLDDDDDDDDDDLLLXXXXXXXXXXXXXXXXXX 12L 1816_13 GAATETTATTTACATETT LLDDLDLLDDDDDDDLLLXXXXXXXXXXXSXXXXX 12M 1816_15 GAATETTATTTACATETT LLDDLDLLDDDDDDDLLLXXXXXXXXXXXXXSXXX 12N 1816_28 GAATETTATTTACATETT LLDDLDLFDDDDDDDLLLXXXXXXXXXXXXXSXXX 12O 1816_41 GAATETTATTTACATETT LLLDLDLLDDDDDDDLLLXXXXXXXXXXXXXXXXX 12P 1816_42 GAATETTATTTACATETT LLDDLDLLDDDDDDDLMLXXXXXXXXXXXXXXXXX 12Q 1816_43 GAATETTATTTACATETT LLDDLDLLDDDDDDDMLLXXXXXXXXXXXXXXXXX 12R 1816_60 GAATETTATTTACATETT LLDDLDLODDDDDDDLLLXXXXXXXXXXXXXXXXX 12S 1816_61 GAATETTATTTACATETT LLODLDLLDDDDDDDLLLXXXXXXXXXXXXXXXXX 12T 1816_64 GAATETTATTTACATCTT LLDDLDLLDDDDDDDFLLXXXXXXXXXXXXXXXXX 12U 1816_65 GAATETTATTTACATCTT LLDDLDLLDDDDDDDOLLXXXXXXXXXXXXXXXXX 12V 1816_68 GAATETTATTTACATEUT LLDDLDLLDDDDDDDLFLXXXXXXXXXXXXXXXXX 12W

TABLE 8B Cortex Midbrain Cerebellum Hippocampus Pons/medulla StriatumMax Max Max Max Max Max EC50 efficacy (% EC50 efficacy (% EC50 efficacy(% EC50 efficacy (% EC50 efficacy (% EC50 efficacy (% Compounds (nM)remaining) (nM) remaining) (nM) remaining) (nM) remaining) (nM)remaining) (nM) remaining) 1856_1 251 33 77 20 434 49 202 41 — 24 103 271813_1 260 22 93 20 347 47 279 30 — 22 89 18 1812_1 307 52 156 28 603 50233 35 — 26 184 32 1809_2 134 57 153 34 511 50 111 46 — 21 93 29 1607_1193 40 89 17 120 42 81 21 — 15 63 26  1122_62 125 56 74 26 226 16 86 46— 19 54 36  1122_67 125 23 79 14 261 27 146 22 — 13 88 19  1122_33 10247 38 16 166 35 79 24 — 17 63 29

TABLE 10 Cortex (A1) Cerebellum Brainstem Midbrain Striatum EC50 Max KDEC50 Max KD EC50 Max KD EC50 Max KD EC50 Max KD Tissue (nM) observed(nM) observed (nM) observed (nM) observed (nM) observed 1 week of1122_67 242 88% 833 74% 196 87% 165 89% 148 77% treatment 1813_1  27861% 966 57% 377 85% 183 90% 118 51% 1100673 391 67% 2012  48% 769 79%279 81% 331 69% 4 week of 1122_67 100 92% 365 81%  81 93%  94 95%  4689% treatment 1813_1  ND ND ND ND ND ND ND ND ND ND 1100673 199 49%1229  33% 419 72% 129 74% 130 35% Spinal cord, Spinal cord, Spinal cord,Hippocampus cervical thoracic lumbar EC50 Max KD EC50 Max KD EC50 Max KDEC50 Max KD Tissue (nM) observed (nM) observed (nM) observed (nM)observed 1 week of 1122_67 243 75% 41 89% 39 90% 54 89% treatment1813_1  341 63% 45 90% 36 92% 48 91% 1100673 516 66% 83 83% 51 83% 6882% 4 week of 1122_67  89 92% 16 93% Imprecise 93% 18 93% treatment1813_1  ND ND ND ND ND ND ND ND 1100673 329 52% 48 83% Imprecise 84% 5684%

TABLE 15Particular antisense oligonucleotide variants of SEQ ID NO: 1122Options for nucleobases, sugar modifications and internucleoside linkages for particular antisenseoligonucleotides according to the invention. The options from which the nucleoside at each specificresidue # in SEQ ID NO: 1122 can be chosen is shown in each line indicated by that residue #,starting from the 5′-end. The selection of a specific nucleobase (“Nucleobase options for residue #”) and a sugar modification (“Sugar modification options for residue #”) defines the nucleoside atthat residue #. The options for the internucleoside linkage between the nucleoside at a specificresidue # and the next residue, starting from the 5′-end, is shown in the column entitled“Backbone modification options for internucleoside linkage #”. Sugar Backbone Residue # Nucleobase options modification optionsmodification options for in SEQ ID for residue # for residue #internucleoside linkage # NO: 1122 A: (A); C: (C); E: (5meC);D: [dR]; F: [fR]; (from 5′-end) (from 5′-end) G: (G); T: (T); U: (U)L: [LR]; M: [MOE]; O: [mR] S: [ssP]; X: [sP] 1 A A A A A A A A A A A A LL L L L L L L L L L L X X X X X X X X X X X X 2 A A A A A A A A A A A AD L D D D D D D D D D D X X X X X X X X X X X X 3 T U T T T T T T T T TT D O D D D D D D D D D D X X X X X X X X X X X X 4 E E E E E E E E E EE C L L L L L L L L L L L O X X X X X X X X X X X X 5 T T T T T T T T TT T T D D D D D D D D D D D D X X X X X X X X X X X X 6 T T T T T T T TT T T T L D L L L L L L L L L L X X X X X X X X X X X X 7 A A A A A A AA A A A A D D D D D D D M D D D D X X X X X X X X X X X X 8 T T T T T TT T T T T T D D D D D D D D D D D D X X X X X X X X X X X X 9 T T T T TT T T T T T T D D D D D D D D D D D D X X X X X X X X X X X X 10 U T T TT T T T T T T T O D D D D D D D D D D D X X X X X X X X X X X X 11 A A AA A A A A A A A A D D D D D D D D D O D D X X S X X X X X X X X X 12 C CC C C C C C C C C C D D D D D D D D D D D D X X X S X X X X X X X X 13 AA A A A A A A A A A A D D D D D D D D D D D D X X X X S X X X X X X X 14T T T T T T T T T T T T D D D D D D D D D D D D X X X X X S X X X X X X15 C C C C C C C C C C C C D D D D D D D D O D D D X X X X X X S X X X XX 16 T T T T T T T T T T T T D L D D D D D D D D D D X X X X X X X X X XX X 17 T T T T T T T T T T T T L D L L L L L L L L L L X X X X X X X X XX X X 18 E E E E E E E E E E C E L L L L L L L L L L F L X X X X X X X XX X X X 19 E E E E E E E E E E E E L L L L L L L L L L L L

TABLE 16Particular antisense oligonucleotide variants of SEQ ID NO: 1816Options for nucleobases, sugar modifications and internucleoside linkagesfor particular antisense oligonucleotides according to the invention.The options from which the nucleoside at each specific residue # in SEQ ID NO: 1122 can be chosen is shown in each line indicated by that residue #, starting from the 5′-end.The selection of a specific nucleobase (“Nucleobase options for residue #”) and a sugar modification(“Sugar modification options for residue #”) defines the nucleoside at that residue #.The options for the internucleoside linkage between the nucleoside at a specific residue #and the next residue, starting from the 5′-end, is shown in the column entitled“Backbone modification options for internucleoside linkage #”.Nucleobase options for Sugar modification options Backbone modificationResidue # in residue # for residue # options for residue #SEQ ID NO: 1816 A: (A); C: (C); E: (5meC); D: [dR]; F:[fR]; L: [LR];(from 5′-end) (from 5′-end) G: (G); T: (T); U: (U) M: [MOE]; O: [mR]S: [ssP]; X: [sP] 1 G G G G G G G G G G G L L L L L L L L L L L X X X XX X X X X X X 2 A A A A A A A A A A A L L L L L L L L L L L X X X X X XX X X X X 3 A A A A A A A A A A A D D D L D D D O D D D X X X X X X X XX X X 4 T T T T T T T T T T T D D D D D D D D D D D X X X X X X X X X XX 5 E E E E E E E E E E E L L L L L L L L L L L X X X X X X X X X X X 6T T T T T T T T T T T D D D D D D D D D D D X X X X X X X X X X X 7 T TT T T T T T T T T L L L L L L L L L L L X X X X X X X X X X X 8 A A A AA A A A A A A L L F L L L O L L L L X X X X X X X X X X X 9 T T T T T TT T T T T D D D D D D D D D D D X X X X X X X X X X X 10 T T T T T T T TT T T D D D D D D D D D D D X X X X X X X X X X X 11 T T T T T T T T T TT D D D D D D D D D D D X X X X X X X X X X X 12 A A A A A A A A A A A DD D D D D D D D D D S X X X X X X X X X X 13 C C C C C C C C C C C D D DD D D D D D D D X X X X X X X X X X X 14 A A A A A A A A A A A D D D D DD D D D D D X S X X X X X X X X X 15 T T T T T T T T T T T D D D D D D DD D D D X X X X X X X X X X X 16 E E E E E E E E C C E L L L L L M L L FO L X X X X X X X X X X X 17 T T T T T T T T T T U L L L L M L L L L L FX X X X X X X X X X X 18 T T T T T T T T T T T L L L L L L L L L L L

Example 17: Transgenic mouse study to assess PK/PD of redesignedcompounds Materials and Methods:

The study was largely performed as described in Example 8. In brief,transgenic animals (B6;CBA-Tg(ATXN3*)84.2Cce/IbezJ male and female mice8 per group (JAX® Mice, The Jackson Laboratory)) of 10-12 weeks of agewere included in the study. The animals were injected with 150 μg ofcompound in 4 μl into the cisterna magna (ICM). The animals weresacrificed after 4 weeks and selected tissues were obtained forevaluation of oligo content as well as knockdown of target transcript.Analysis methods were as described in Example 8.

Results:

The results are presented in Table 17 below.

TABLE 17 Efficacy results. Cortex Midbrain Cerebellum Pons/medulla MaxMax Max Max Compound ID EC50 efficacy (% EC50 efficacy (% EC50 efficacy(% EC50 efficacy (% NO (nM) remaining) (nM) remaining) (nM) remaining)(nM) remaining) 1122_91 894 77 69 52 616 63 134 41  1122_107 1385 35 7320 388 22 95 21 1816_28 1791 71 442 62 1682 79 664 70 1816_42 8587 8614763 73 1990 76 598 69  1122_156 812 69 75 43 330 56 105 40 1816_651633 73 453 55 1147 73 1053 59 *ND Value was not possible to determinedue to the available data

Table 17 shows the readout from the study described in Example 17. AnEC50 value was calculated for each compound in each of the obtainedbrain regions. Also, the maximally obtained target knockdown washighlighted within each group/tissue showing the remaining percentage oftarget mRNA relative to the saline control group.

The outcome of the evaluation resulted in compounds with attractiveprofiles in terms of efficacy and potency, i.e. with a low value forEC50 and a low value in the column for “max efficacy (% remaining)”. Amost attractive compound based in these criteria is 1122_107 with bestefficacy across all tissues and EC50 values in the lowest half of allthe measured values. Another attractive compound based on efficacy andpotency is 1122_156.

Example 18: Comparative transgenic mouse study evaluation oftolerability Materials and Methods:

A further in vivo study was conducted to evaluate tolerability of testcompounds. The study was largely performed as described in Example 10.In short, wild type animals (C57BL/6J) of around 7 weeks were includedin the study. Animals, all female, arrived from The Jackson Laboratory,Bar Harbor, Me., USA were used. The mice were injected with thecompounds via intracisternal (ICM) administration. After a period of 4weeks, animals were euthanized and selected tissues were collected. Theanimals were injected with a dose 300 μg compound in WT animals.

Functional Observation Battery (FOB) scores from the animals wereobtained On Day 1 at 1, 4, and 24±2 hours post dosing, then again priorto scheduled termination.

The FOB (functional observation Battery) score

The FOB score is a non-invasive tool describing various neurobehavioraland activity related parameters.

Procedure:

Technicians were blinded to group belongings. Animals were observed forat least 1 minute in their home cage to record scores of the belowmentioned parameters. Body temperature was recorded using a rectalthermometer.

The evaluation, except body temperature, was performed while the animalremained in its home cage; the open-field testing box will not be used.

Activity: Excitability: Autonomic: Arousal/Alertness ConvulsionsPalpebral Stereotypy Closure/Ptosis Posture/Body Carriage Erected FurNeuromuscular: Physiological: Gait/Mobility Respiration Tremor BodyTemperature

Based on the evaluation of the animals they were scored as being eithermild (in same range as saline control group), moderate or severelyimpacted by the administration of compound.

Administration of Compound

Dose Route: Stereotaxic intracerebroventricular (ICV) injection. Dosevolume was 10 μl. The dose was administered using a 10 μL Hamiltonsyringe with attached 22 gauge needle over one injection at a target of1 μL/sec.

Results:

The list of compounds is provided in Table 18 listing the compound IDnumber, the injected amount of test compound and a rating (mild,moderate or severe) of the in life observations, with mild meaning no oronly few signs of adverse events, and severe meaning severe observationin the group with potential of premature takedown of animals in thegroup.

TABLE 18 Tolerability results. In life tolerability No of PrematureCompound ID Dose observations animals* termination Saline — Mild 6 01122_91 300 μg Moderate 7 0  1122_107 300 μg Moderate 7 0  1122_172 300μg Moderate 7 0 1816_28 300 μg Severe 3 1 1816_42 300 μg Severe 3 01816_43 300 μg Severe 3 1  1122_154 300 μg Moderate 6 0  1122_156 300 μgMild 6 0 1813_15 300 μg Severe 3 1 1605_4  300 μg Mild 6 0 1816_65 300μg Severe 3 1 1605_2  300 μg Mild 6 0 1816_64 300 μg Severe 3 3 *Forhumane reasons 3 animals were dosed and depending on tolerabilityadditional 3-4 animals were dosed on the following day.

Compound ID NO: 1813_15 has the following structure (HELM notation):

1813_15[LR]([5meC])[sP]•[LR](T)[sP]•[LR](G)[sP]•[dR](T)[sP]•[dR](A)[sP]•[mR](C)[sP]•[mR](A)[sP]•[dR](C)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](T)[sP]•[dR](A)[sP]•[dR](C)[sP]•[dR](A)[sP]•[LR](T)[sP]•[LR](T)[sP]•[LR]([5meC])

From Table 18, different outcomes relating to acute tolerability wereobserved for the different compounds, with some compounds showing “mild”signs (like the saline group animals) including compound ID NOs1122_156, 1605_4 and 1605_2, some compounds showing “moderate” signslike compound ID NOs 1122_107 and 1816_64, and other compounds againshowing “severe” signs like compound ID NOs 1816_43 and 1816_64.

A histopathological evaluation (macroscopic and microscopic) of the micewas conducted following termination of the animals. The aim of theevaluation was to identify compound related toxicological events, bothof subacute and late onset nature. The evaluation included thepathologist's assessment of possible compound related neuronal changesbased and hematoxylin and eosin stains and by Fluoro-Jade stain toassess signs of neuronal degeneration.

Example 19: In vitro duration of action evaluation of LNAoligonucleotides in a time course, dose range experiment in humaniPSC-derived neurons Materials and Methods:

The compounds listed in Table 19 and Table 20 were submitted to an invitro evaluation of potency and efficacy in a time-course experimentalsetup. The study was largely performed as described in Example 9, withdifferent time points and compounds.

The iCell® GlutaNeuron cells were prepared and maintained essentially asdescribed in Example 5 & Table 2. 96-well cell culture plates werecoated with Poly-L-Ornithine (0.01%) (Sigma-P4957), 100 μl/well for 4hours, rinsed 3 times with PBS and coated with Laminin (RocheDiagnostic, 11243217001) 0.5 mg/ml diluted 1:500 in PBS overnight at 4degrees Celsius. The cells were treated and maintained as perrecommendation by the vendor using the provided protocol: iCell®GlutaNeurons, User's Guide, Document ID: X1005, Version 1.2, CellularDynamics, Fujifilm; available at https addresscdn.stemcell.com/media/files/manual/MADX1005-icell_glutaneurons_users_guide.pdf(accessed on e.g. 10 Nov. 2020). Cells were grown for 7 days beforeaddition of the oligonucleotide. Compounds were added to the cells frompre-dilution plates (compound diluted in PBS) to reach the desired finalconcentration. The concentrations used were an 8-step halflog with thefollowing concentrations (nM): 31.6; 10; 3.2; 1; 0.32; 0.1; 0.03; 0.01.

Compounds used are listed in Table 19 and Table 20.

The following primers were used to assess the level of knockdown of thetarget mRNA of hATXN3.

Human ATXN3 pre-mRNA using the qPCR assay: customdesign “(ATXN3_exon_8-9(1)”, PrimeTime ® XL qPCR Assay (IDT).(SEQ ID NO: 1134) Probe: 5′/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCT AAGT/31ABkFQ/-3′ (SEQ ID NO: 1135)Primer 1: 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′ (SEQ ID NO: 1136)Primer 2: 5′-CATGGAAGATGAGGAAGCAGAT-3′Human TBP pre-mRNA using the qPCR assay:“Hs.PT.58v.39858774”, PrimeTime ® XL qPCR Assay (IDT) (SEQ ID NO: 1131)Probe: 5′-/5HEX/TGA TCT TTG/ZEN/CAG TGA CCC AGC ATC A/3IABkFQ/-3′(SEQ ID NO: 1132) Primer 1: 5′-GCT GTT TAA CTT CGC TTC CG-3′(SEQ ID NO: 1133) Primer 2: 5′-CAG CAA CTT CCT CAA TTC CTT G-3′

Cells were harvested at 4 days, 20 days, 29 days, and 40 days afteroligo treatment, and RNA extraction and qPCR was performed as describedfor Example 1, using the ATXN3 primer assay described in Example 5. Therelative ATXN3 mRNA expression levels were determined as % of control(medium-treated cells), i.e. the lower the value the larger theinhibition.

Results:

The results are shown in Table 19 and Table 20. Table 19 presents thepotency of the tested compounds (EC50 value (nM)) over the indicatedtime points post dosing. Table 20 presents the data as percent remainingATXN3 mRNA relative to PBS treated cells after dosing with 3.204compound for the indicated time points post dosing.

TABLE 19 EC50 in hiPSC-derived neurons EC50 in hiPSC-derived neurons, nMCMP ID Day 4 Day 20 Day 29 Day 40  1122_154 56.5 42.4 89.3 314.4 1122_156 53.2 33.4 50.1 88.7 1816_28 128.4 653.3 926.1 1465.0 1605_4 76.7 33.6 47.3 71.8 1816_65 70.9 51.0 184.2 692.3 1122_91 115.5 76.9171.6 748.0  1122_107 74.6 20.7 19.0 35.1  1122_172 66.1 50.1 90.4 306.11816_42 196.0 262.0 546.3 830.7 1816_43 97.2 68.5 136.1 709.8 Negativecontrol ND ND ND ND *ND Value was not possible to determine due to theavailable data

The calculated EC50 values for each compound for each of the time pointsare shown in Table 19. From the data it can be seen that there was awide range of obtained EC50 values for the different compounds at thedifferent time points. Generally there were some compounds showing highEC50 values indicating a low potency which also decreases (higher value)over time. Examples of these are compound ID NOs 1816_28, and 1122_172.On the other hand, there were also compounds which maintained a highpotency (low value for EC50) over the duration of 40 days, showing EC50values below 100 nM. Examples of these compounds are compound ID NOs1122_156, 1605_4 and 1122_107. A low EC50 value is a beneficial propertyof a compound because it indicates that a lower amount of compound isrequired to elicit an effect.

TABLE 20 Efficacy in hiPSC-derived neurons following addition of 3.2 μMcompound. % remaining transcript in hiPSC-derived neurons aftertreatment with 3.2 μM compound CMP ID Day 4 Day 20 Day 29 Day 40 1122_154 6.3 4.4 11.5 19.0  1122_156 6.8 5.0 7.8 16.0 1816_28 13.2 29.632.3 50.5 1605_4  8.7 3.3 2.9 4.5 1816_65 7.5 8.2 13.1 22.7 1122_91 10.58.0 15.5 32.5  1122_107 8.3 4.5 4.3 6.0  1122_172 7.1 4.8 8.2 22.01816_42 9.8 15.2 23.6 46.3 1816_43 7.1 7.8 9.8 20.9 Negative control93.5 95.1 94.1 115.8

Table 20 show the observed levels of remaining mRNA (% remainingtranscript compared to PBS control) in the cells following a treatmentof the cells with 3.204 of compound as described above. The evaluationwas performed at multiple time points after compound addition. From thetable it is clear that many of the compounds were able to maintain asuppression of the level of mRNA over the duration of 40 days followinga single exposure to compound. A number of compounds were able tomaintain a suppression of more than 90% for the duration of 40 days suchas compound ID NOs 1605_4 and 1122_107. Furthermore, compound ID NO1122_156 showed a high level of knockdown for the duration of 40 days. Ahigh level of knockdown over a long period indicates a long duration ofaction and potential for a more infrequent administration.

Example 20: In vivo assessment in transgenic animals of efficacy andduration of action Materials and Methods:

A further in vivo study was performed using compound ID NOs 1605_4,1122_107 and 1122_156. The study used male and femaleB6;CBA-Tg(ATXN3*)84.2Cce/IbezJ mice with the compounds administered viaintra cisterna magna (ICM) administration. At three time points aftercompound administration, 4, 8 and 11 weeks, animals were euthanized andterminal plasma samples and tissues were collected.

Animal Care

In vivo activity and tolerability of the compounds were tested in 62B6;CBATg(ATXN3*)84.2Cce/IbezJ male and female mice (JAX® Mice, TheJackson Laboratory) at the age of 10 weeks. Following arrival, animalswere housed in groups up to 5 in individually vented cages (IVC,38×22×15 cm) in a temperature (22±2° C.) and humidity (55±15%)controlled environment on a 12 hour light cycle (07.00-19.00 h). Malesand females were kept in separate cages. Standard diet (SDS Diets, RM1PL) and domestic quality mains water were available ad libitum. Ifrequired, animals received soaked chow and/or Royal Canin in addition tostandard diet as part of pamper care. The experiments were conducted instrict accordance with the Guide for the Care and Use of LaboratoryAnimals (National Research Council 2011) and were in accordance withEuropean Union directive 2010/63 and the Dutch law.

Administration Route-Intra-cisterna Magna injections.

The compounds were administered to mice by intra cisterna magna (ICM)injections. Mice were anesthetized using isoflurane (2.5-3% and 500mL/min 02). Before surgery, Finadyne (1 mg/kg, s.c.) was administeredfor analgesia during surgery and the post-surgical recovery period. Amixture of bupivacaine and epinephrine was applied to the incision siteand periost of the skull for local analgesia. Animals were placed in astereotaxic frame (Kopf instruments, USA) and an incision made at theback of the head towards the neck. Then, the skin was spread and thecoordinates marked prior to drilling a hole in the occipital bone of theskull, where a cannula was placed. Next, the compounds were injectedinto the cisterna magna (ICM). A volume of 10 μL of the assigned testitem was injected over 30 seconds. After injection, the needle andcannula were held in place for 30 seconds to ensure no back flowoccurred. The cannula was then retracted, the hole was covered with skinand the incision was closed by sutures. Animals were placed in a warmenvironment until recovered from the procedure. The compounds wereadministered as a single dose as listed in Table 21. Each groupcontained 4-6 animals.

TABLE 21 Treatment regimes. Dose of compound in 10 μl Weeks of CompoundID NO volume treatment 0.9% Saline — 4 1605_4  20 μg/μl equals 200 μg 4,8, 11 compound 1122_107 20 μg/μl equals 200 μg 4, 8, 11 compound1122_156 20 μg/μl equals 200 μg 4, 8,11 compound

At the end of the experiment, after week 4, 8 and 11, the animals wereeuthanized by Euthasol® overdose. Terminal plasma was collected inLi-Hep tubes. Terminal tissues were harvested from the animals and weredissected on a chilled surface. Half of the tissue samples were storedin 2.0 mL Safe-Lock tubes, PCR clean, pre-weighted and precooled.Immediately after collection, samples were weighed and flash frozen inliquid N2 prior to storage at −80° C. The other half was fixed in 4% PFAfor 72 hours and subsequently transferred to 70% ethanol awaitingshipment. Tissue dissection and collection was performed, collectingtissue from a range of tissues: Cortex, Cerebellum, Brainstem, Midbrainand Striatum. There were no signs of acute toxicity of any of theadministered compounds and hence no premature termination of animals dueto compound related toxicity.

Analysis of in vivo samples: Description of tissue preparation forcontent measurement and qPCR was performed as per Example 8. The medianknockdown of target mRNA achieved was recorded as percent remainingtarget transcript relative to saline control group—this data is providedin Table 22.

Results:

TABLE 22 Knock down data for each compound for each time point. CortexCerebellum Brainstem Midbrain Striatum Median KD Median KD Median KDMedian KD Median KD (% remaining (% remaining (% remaining (% remaining(% remaining Tissue transcript) transcript) transcript) transcript)transcript) 4 week of  1605_4 - 200 μg 19 34 8 5 34 treatment 1122_107 -200 μg 35 31 14 8 41 1122_156 - 200 μg 53 44 16 12 53 8 week of 1605_4 - 200 μg 56 41 22 12 67 treatment 1122_107 - 200 μg 43 30 25 1733 1122_156 - 200 μg 76 46 46 38 72 11 week of  1605_4 - 200 μg 65 50 3821 73 treatment 1122_107 - 200 μg 82 41 46 39 75 1122_156 - 200 μg 99 7070 75 100

Overall. it can be seen that the brainstem and the midbrain were thebrain areas targeted most efficiently across all compounds when focusingon knock down efficacy.

Example 21: WT and polyQ Ataxin 3 protein levels in human SCA3 patientderived fibroblasts treated with selected oligonucleotides (ASO)Materials and Methods:

Reference compounds 1287095 and 1102579 referred to in this Examplecorrespond to the oligonucleotides disclosed as Compound No. 1287095 inWO2020/172559 A1 and Compound No. 1102579 in WO2019/217708 respectively.

This experiment was performed to investigate the efficacy of knock downof the tested antisense oligonucleotides. The study was largelyperformed as described in Example 12.

The evaluation was performed in the SCA3 patient derived fibroblasts,allowing for an assessment of the efficacy on the disease causingataxin3 allele and the ataxin3 WT allele.

The cell line used for the ASO treatment was human SCA3 patient derivedfibroblasts (GM06153—Coriell Institute). Twenty thousand cells wereseeded per well in a 24 well plate with a total volume of 1 ml. ASOswere added immediately after to a final concentration of 5 μM (gymnoticuptake). After 4 days of incubation, cells were washed twice with PBS,and harvested in 50 μl LDS sample buffer (NuPAGE, Thermo Scientific)with addition of 50 mM fresh DTT.

Western blots were performed on the capillary-based immunoassay platform(WES, ProteinSimple) using a WES 12-230 kDa Wes Separation Module. Celllysates were diluted 10×in Sample load buffer (ProteinSimple) prior toloading on the cartridge. Primary antibody for Ataxin 3 (rabbitmonoclonal antibody, prod. #702788 from Invitrogen) and for HPRT (rabbitmonoclonal antibody, cat. #Ab109021 from Abcam). Both antibodies wereused in 1/100 dilutions. Goat anti-rabbit HRP conjugate (Part. #DM-001,ProteinSimple) was used as secondary antibody.

Compass software (ProteinSimple) was for quantification of the proteinbands.

Results:

Ataxin 3 antibody recognized both isoforms, and the intensity (areaunder peak) was normalized to the protein input based on the signal fromHPRT. The raw data are shown in FIGS. 13 and 14, and are quantified asdescribed in FIG. 15.

Difference between allele selectivity was evaluated using an ordinaryt-test, (unpaired, two-tailed, homoscedastic, calculated using MicrosoftExcel, 2016, version 160.5227.1000) for each compound comparing thelevel of each detected allele. A difference (α=0.05) was observed forcompound ID NOs 1287095 and 1122_156.

The effect on protein knock down was evaluated for each allele (e.g.wild type and polyQ expanded allele, individually) and compared to thenegative control using an ordinary one-way ANOVA test with Dunnettcorrection for multiple testing (Calculated using GraphPad Prism,version 8.4.2 (679)). Some level of a decrease in protein from both WTand polyQ allele was observed for all compounds except for compound IDNO 1287095, where no decrease was observed for either allele using aneffective concentration of compound of 504.

In summary it can be observed in FIGS. 13 to 15 that compound ID NOs1605_2, 1605_4, 1122_107 and 1122_156 effectively induce a knockdown oftarget protein—both wild type and polyQ expanded version—and thatcompound ID NO 1122_156 additionally has a statically significantincreased effect on the polyQ expanded allele. A higher activity on thedisease causing polyQ extended Ataxin 3 than the WT Ataxin 3 ispreferable as it allows a selective reduction of the disease causingallele. The reference compounds 1287095 and 1102579 did not induce asignificant reduction of either of the versions of the target proteinunder the tested conditions.

This experimental setup also measured the resulting effect on mRNA levelfollowing treatment with the compounds shown in FIG. 15. The data arenot shown, but the analysis was performed exactly as described inExample 22. The effect of the compounds on the ATXN3 mRNA level followedthe same pattern as did the protein levels. This means that when a highlevel of protein knock down was observed, there was also observed a highlevel of mRNA knock down and vice versa, as shown in Example 22.

Example 22: Knock down of WT Ataxin 3 protein levels in human SK-N-AScell line treated with selected oligonucleotides (ASO) Materials andMethods:

This experiment was performed to investigate the efficacy of efficacy ofknock down of the tested antisense oligonucleotides. The evaluation wasperformed in SK-N-AS cells (cell line listed in Table 2), allowing foran assessment of the efficacy on ataxin3 alleles and related proteinproduction. Twenty five thousand cells were seeded per well in a 24 wellplate with a total volume of 500 μl. In three replicate wells, ASOs wereadded immediately after to a final concentration of 5 μM (gymnoticuptake). The reference compounds 1287095 and 1102579 were additionallytested in a concentration of 15 μM. After 4 days of incubation, cellswere washed twice with PBS, and harvested in 100 μl LDS sample buffer(NuPAGE, Thermo Scientific) with addition of 50 mM fresh DTT. Westernblots were performed on the capillary-based immunoassay platform (WES,ProteinSimple) using a WES 12-230 kDa Wes Separation Module. Cell lysatewere diluted 10× in Sample load buffer (ProteinSimple) prior loading onthe cartridge. Primary antibody for Ataxin 3 (rabbit monoclonalantibody, prod. #702788 from Invitrogen) and for HPRT (rabbit monoclonalantibody, cat. #Ab109021 from Abcam). Both antibodies were used in 1/100dilutions. Goat anti-rabbit HRP conjugate (Part. #DM-001, ProteinSimple)was used as secondary antibody.

Compass software (ProteinSimple) was for quantification of the proteinbands.

The effects of the above mentioned compounds were also evaluated ontranscript level by digital droplet PCR (ddPCR) analysis in a similarsetup. Cells were treated similarly to the cells used for proteindetermination with respect to compound concentrations and time points.The SK-N-AS cell line was used for the ASO treatment, with 10.000 cellsseeded per well in a 96 well plate with a total volume of 0.1 ml. ASOswere added immediately after to a final concentration of 5 μM and forcompounds 1287095 and 1102579 also with 15 μM (gymnotic uptake). After 4days of incubation, cells were washed twice with PBS, and harvested in200 μl RIPA buffer (Thermo Scientific, Pierce). The purified RNA wasdenatured before cDNA synthesis. cDNA was created using the iScriptAdvanced cDNA Synthesis Kit for RT-qPCR (Biorad) according to themanufacturer's instructions. Measurements of the expression levels ofthe target genes was done by droplet digital PCR using the QX200 dropletsystem (Bio-Rad) together with the QX200 software standard edition.

The following assays were used for the analysis:

qPCR probe and primers set: PrimeTime ® XL qPCR Assay (IDT)-ATXN3_exon_8-9(1) (SEQ ID NO: 1134)Probe: 5′-/56-FAM/CTCCGCAGG/ZEN/GCT ATTCAGCT AAGT/31ABkFQ/-3′(SEQ ID NO: 1135) Primer 1: 5′-AGT AAGATTTGT ACCTGATGTCTGT-3′(SEQ ID NO: 1136) Primer 2: 5′-CATGGAAGATGAGGAAGCAGAT-3′Reference gene was hHPRT PrimeTime ® XL qPCR Assay (IDT)-Hs.PT.58v.45621572 (SEQ ID NO: 1993)Probe: 5′-/5HEX/AGCCTAAGA/ZEN/TGAGAGTTCAAGTTGAGTT TGG/3IABkFQ/-3′(SEQ ID NO: 1994) Primer 1: 5′-GCGATGTCAATAGGACTCCAG-3′(SEQ ID NO: 1995) Primer 2: 5′-TTGTTGTAGGATATGCCCTTGA-3′

The resulting evaluation of the remaining mRNA level following compoundtreatment is presented in FIG. 19.

Results:

Ataxin 3 antibody recognizes the wild type Ataxin 3 protein expressed bythe cells, and the intensity (area under peak) was normalized to theprotein input based on the signal from HPRT. The raw data are shown inFIG. 16 and FIG. 17 (Reference compounds including negative and positivecontrols), and the quantification is shown in graphical format in FIG.18.

The effect on protein knock down for each of the tested compounds wasevaluated by comparison to the negative PBS control using an ordinaryone-way ANOVA test with Dunnett correction for multiple testing(Calculated using GraphPad Prism, version 8.4.2 (679)). A decrease inprotein levels were observed for all compounds with p-value<0.001compared to PCR control samples. From the raw WES data (FIG. 16 and FIG.17) and the quantification (FIG. 18) it is clear that there arepronounced differences in the level of protein knock down between thecompounds. The compounds 1605_2, 1605_4, 1122_107 and 1122_156 were veryefficacious in knocking down Ataxin 3 protein using the effectiveconcentrations of 504. The reference compounds 1287095 and 1102579 wereboth less efficacious. Reference compounds 1287095 and 1102579 wereunable to induce the same level of effect (level of protein knockdown)as the best performing compounds even when used in a disadvantageouslyhigh concentration (15 μM, 3 times higher than the other respectivedoses of 5 μM).

FIG. 19 shows the efficacy of the compounds with the listed appliedconcentrations in terms of knockdown of the ATXN3 encoding transcript.The mRNA knock down follows the same pattern as observed for the proteinquantification shown in FIG. 18. Again it is observed that the compoundID NOs 1605_2, 1605_4, 1122_107 and 1122_156 are more efficacious atreducing ATXN3 mRNA levels compared to compounds 1287095 and 1102579.Again, a three times higher applied concentration of compounds 1287095and 1102579 still did not obtain a level of efficacy which was as highas that of the best performing compounds.

1. An antisense oligonucleotide selected from the group consisting ofCompound ID Nos. 1122_107, 1122_156, 1122_91, 1122_154, 1122_155,1122_157, 1122_158, 1122_167, 1122_172, 1122_175, 1122_294, 1122_296,1816_13, 1816_15, 1816_28, 1816_41, 1816_42, 1816_43, 1816_60, 1816_61,1816_64, 1816_65, and 1816_68, or a pharmaceutically acceptable saltthereof.
 2. An antisense oligonucleotide according to claim 1 of thefollowing chemical annotation: (a)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([m R])U_([sP]).^([dR])(A)_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C)_([sP]).^([LR][5me])C(SEQ ID NO:1122, wherein residue 10 is U) (Compound ID No. 1122_91); (b)^([LR])A_([sP]).^([LR])A_([sP]).^([mR])U_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([LR])T_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122, wherein residue 3 is U) (Compound ID No. 1122_107); (c)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([ssP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_154); (d)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_155); (e)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([ssP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_156); (f)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([ssP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_157); (g)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([d R])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([ssP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_158); (h)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([MOE])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_167); (i)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR])[5meC]_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([ssP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_172); (j)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_175); (k)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([fR])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_294); (l)^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([dR])A_([sp]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([s P]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([dR])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR][5me])C_([sP]).^([LR][5me])C(SEQ ID NO:1122) (Compound ID No. 1122_296); (m)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([ssP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_13); (n)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([ssP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_15); (o)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([fR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_28); (p)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_41); (q)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([MOE])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_42); (r)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([MOE][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_43); (s)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([mR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_60); (t)^([LR])G_([sP]).^([LR])A_([sP]).^([mR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_61); (u)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([fR])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_64); (v)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([mR])C_([sP]).^([LR])T_([sP]).^([LR])T(SEQ ID NO:1816) (Compound ID No. 1816_65); or (w)^([LR])G_([sP]).^([LR])A_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([dR])T_([sP]).^([LR])T_([sP]).^([LR])A_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])T_([sP]).^([dR])A_([sP]).^([dR])C_([sP]).^([dR])A_([sP]).^([dR])T_([sP]).^([LR][5me])C_([sP]).^([fR])U_([sP]).^([LR])T(SEQ ID NO:1816, wherein residue 17 is U)(Compound ID No. 1816_68), oris a pharmaceutically acceptable salt thereof, wherein [LR] is abeta-D-oxy-LNA nucleoside, [LR][5me]C is a beta-D-oxy-LNA 5-methylcytosine nucleoside, [dR] is a DNA nucleoside, [sP] is aphosphorothioate internucleoside linkage (stereo undefined) [ssP] is astereodefined Sp phosphorothioate internucleoside linkage [mR] is a2′-O-methyl nucleoside, [MOE] is a 2′-O-methoxyethyl nucleoside, and[fR] is a 2′-fluoro nucleoside.
 3. The antisense oligonucleotideaccording to claim 1, which is the antisense oligonucleotide shown inFIG. 12A (Compound ID No. 1122_91); or a pharmaceutically acceptablesalt thereof.
 4. The antisense oligonucleotide according to claim 1,which is the antisense oligonucleotide shown in FIG. 12B (Compound IDNo. 1122_107); or a pharmaceutically acceptable salt thereof.
 5. Theantisense oligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12C (Compound ID No. 1122_154); or apharmaceutically acceptable salt thereof.
 6. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12D (Compound ID No. 1122_155); or apharmaceutically acceptable salt thereof.
 7. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12E (Compound ID No. 1122_156); or apharmaceutically acceptable salt thereof.
 8. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12F (Compound ID No. 1122_157); or apharmaceutically acceptable salt thereof.
 9. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12G (Compound ID No. 1122_158); or apharmaceutically acceptable salt thereof.
 10. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12H (Compound ID No. 1122_167); or apharmaceutically acceptable salt thereof.
 11. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12I (Compound ID No. 1122_172); or apharmaceutically acceptable salt thereof.
 12. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12J (Compound ID No. 1122_175); or apharmaceutically acceptable salt thereof.
 13. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12K (Compound ID No. 1122_294); or apharmaceutically acceptable salt thereof.
 14. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12L (Compound ID No. 1122_296); or apharmaceutically acceptable salt thereof.
 15. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12M (Compound ID No. 1816_13); or apharmaceutically acceptable salt thereof.
 16. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12N (Compound ID No. 1816_15); or apharmaceutically acceptable salt thereof.
 17. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12O (Compound ID No. 1816_28); or apharmaceutically acceptable salt thereof.
 18. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12P (Compound ID No. 1816_41); or apharmaceutically acceptable salt thereof.
 19. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12Q (Compound ID No. 1816_42); or apharmaceutically acceptable salt thereof.
 20. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12R (Compound ID No. 1816_43); or apharmaceutically acceptable salt thereof.
 21. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12S (Compound ID No. 1816_60); or apharmaceutically acceptable salt thereof.
 22. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12T (Compound ID No. 1816_61); or apharmaceutically acceptable salt thereof.
 23. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12U (Compound ID No. 1816_64); or apharmaceutically acceptable salt thereof.
 24. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12V (Compound ID No. 1816_65); or apharmaceutically acceptable salt thereof.
 25. The antisenseoligonucleotide according to claim 1, which is the antisenseoligonucleotide shown in FIG. 12W (Compound ID No. 1816_68); or apharmaceutically acceptable salt thereof.
 26. A conjugate comprising anoligonucleotide according to claim 1, and at least one conjugate moietycovalently attached to said oligonucleotide; or a pharmaceuticallyacceptable salt thereof.
 27. A pharmaceutical composition comprising anoligonucleotide according to claim 1 or a conjugate thereof and apharmaceutically acceptable diluent, solvent, carrier, salt and/oradjuvant.
 28. An in vivo or in vitro method for modulating ATXN3expression in a target cell which is expressing ATXN3, said methodcomprising administering an oligonucleotide selected from the groupconsisting of Compound ID Nos. 1122_91, 1122_107, 1122_154, 1122_155,1122_156, 1122_157, 1122_158, 1122_167, 1122_172, 1122_175, 1122_294,1122_296, 1816_13, 1816_15, 1816_28, 1816_41, 1816_42, 1816_43, 1816_60,1816_61, 1816_64, 1816_65, and 1816_68, a conjugate, a salt, or apharmaceutical composition thereof in an effective amount to said cell.29. A method for treating or preventing a disease comprisingadministering a therapeutically or prophylactically effective amount ofan oligonucleotide selected from the group consisting of Compound IDNos. 1122_91, 1122_107, 1122_154, 1122_155, 1122_156, 1122_157,1122_158, 1122_167, 1122_172, 1122_175, 1122_294, 1122_296, 1816_13,1816_15, 1816_28, 1816_41, 1816_42, 1816_43,1816_60,1816_61,1816_64,1816_65, and 1816_68, a conjugate, a salt, or apharmaceutical composition thereof to a subject suffering from orsusceptible to the disease.
 30. The method of claim 29, wherein thedisease is spinocerebellar ataxia, such as spinocerebellar ataxia 3,such as Machado-Joseph disease
 31. The oligonucleotide, a conjugate, asalt, or a pharmaceutical composition thereof according to claim 1 foruse in medicine.
 32. The oligonucleotide, a conjugate, a salt, or apharmaceutical composition thereof according to claim 1 for use in thetreatment or prevention of spinocerebellar ataxia, such asspinocerebellar ataxia 3, such as Machado-Joseph disease, (MJD).
 33. Useof the oligonucleotide, a conjugate, a salt, or a pharmaceuticalcomposition thereof according to claim 1 for the preparation of amedicament for treatment or prevention of spinocerebellar ataxia, suchas spinocerebellar ataxia 3, such as Machado-Joseph disease.